The Future of Bladder Control--Intravesical Drug Delivery, a Pinch of Pepper, and Gene Therapy

Treatment Update

TREATMENT UPDATE The Future of Bladder Control— Intravesical Drug Delivery, a Pinch of Pepper, and Gene Therapy Matthew O. Fraser, PhD,* John P. Lavelle, MB, FRCSI,‡ Michael S. Sacks, PhD,† Michael B. Chancellor, MD* Departments of *Urology and †Engineering, University of Pittsburgh School of Medicine, Pittsburgh, PA; ‡Division of Urology, University of North Carolina, Capel Hill, NC The incidence of urinary incontinence and overactive bladder problems will continue to grow as the population ages. Future treatments are likely to include an implantable drug delivery system, gene therapy, and the intravesical use of the vallinoids capsaicin and resiniferatoxin (RTX). An understanding of the urothelium is essential for effective design of these therapies. Intravesical anticholinergic drug treatment is currently not widely used, but intravesical pumps are under development to provide less cumbersome treatment methods and will provide nonsurgical options for patients who cannot tolerate oral anticholinergic agents. Research on the use of capsaicin as an intravesicular drug has had limited success, but trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. RTX is as effective as capsaicin but without side effects, such as pain and inflammatory neuropeptide release. RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. Gene therapy will change the practice of urology by addressing the deficiencies that cause symptoms rather than attacking the symptoms themselves. [Rev Urol. 2002;4(1):1–11] © 2002 MedReviews, LLC Key words: Overactive bladder • Urothelium • Drug absorption • Intravesical vallinoid therapies rinary incontinence and the overactive bladder (OAB) are becoming internationally “hot” topics in the pharmaceutical industry. There are two reasons for the recent spotlight on OAB. First, the tremendous number of patients with this problem is just now becoming recognized and the potential economic impact is staggering. In the United States, there are an estimated 17 million men and women with bladder control problems, many of whom suffer from OAB. It costs an estimated $26 billion a year in the United States to manage U VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY 1 Future of Bladder Control continued OAB, according to the Agency for Health Care Policy and Research.1 With the continued aging of the populations in all developed countries, the problems associated with OAB will certainly continue to grow. The second reason why there is such interest in the OAB is the recent availability of improved treatment options. There had been a lull in the development of new treatment options after the introduction of oxybutynin chloride in 1972. However, with the recent introduction of tolterodine (Detrol, Pharmacia & Upjohn) and the once-a-day controlled-release oxybutynin XL (Ditropan XL, Alza), physicians are now armed with better tools to help patients with OAB. In this article, we speculate about future treatment methods to conquer urinary incontinence and OAB. For example, already under development is an implantable bladder drug delivery system that can deliver a constant therapeutic dose of an anticholinergic drug for 30 days. Gene therapy is also a possible way to deliver beneficial proteins or cytokines into the lower urinary tract. Our laboratory has some successful preliminary results with gene therapy for voiding dysfunction in the rat, and we believe urologists will be treating patients with gene therapy through a cystoscope by 2010. In the near future we foresee the novel intravesical vanilloid therapies, capsaicin and resiniferatoxin, as challenging the concept of how we treat OAB. We will begin to use such drugs to decrease or prevent the sensation of urgency and frequency leading to urge incontinence rather than using anticholinergic drugs to relax the already-spastic bladder. This is analogous to preventing a problem from occurring rather than trying to minimize the damage once the “horse is out of the barn.” The Amazing Urothelium We start with a brief review of the amazing urothelium. There is a recent explosion of interest in the oftenneglected urothelium. Understanding of the urothelium is important in order to design effective intravesical drug delivery. The functions of the bladder are accommodation of urine, storage of urine, maintenance of urine composition, and facilitation of voiding at appropriate time intervals. The urothelium participates physiologically in all aspects of these functions and as such can no longer be thought of as an inert barrier between urine and plasma. The urothelium consists of a variable number of layers of cells, depending on the species examined (Figure 1). In Figure 1. Diagrammatic representation of the bladder urothelium. The lumen of the bladder is in the upward direction, while the lamina propria is below. The glycosaminoglycan layer is shown as discontinuous for illustrative purposes, enabling labeling of deeper structures. Glycosaminoglycan Layer Uroplakin Plaques and Discoidal Vesicles Zonula Occludens Umbrella Cell Stratum Intermediate Cell Stratum Basal Cell stratum Basal Lamina 2 VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY humans, there are up to six to eight layers of cells.2 In all mammalian species, there are three distinct zones, which include of a layer of basal cells, that are germinal in nature and approximately 5 m to 10 m in diameter. Intermediate cells are superficial to these and are approximately 20 m in diameter.3 Finally, a layer of umbrella cells forms the luminal surface of the urothelium. These cells are the largest epithelial cells in the body, measuring from 100 m to 200 m in diameter. They are polyhedral in shape (generally hexagonal), and can flatten and increase surface area with stretching. They may also be multinucleated.4 The surface of the umbrella cells is covered with a glycosaminoglycan (GAG) layer. Bladder urothelial permeability depends on a number of factors. These are passive diffusion, osmotically driven diffusion, active transport, and the inertness of the membrane to the solutes to which it is exposed. In the following section we will review the most recent studies on the glycosaminoglycan layer and the unique umbrella cell, and how these two layers may be important in bladder permeability and barrier function. Glycosaminoglycan Layer (GAG) The GAG layer has been the controversial subject of urothelial barrier function. Parsons and associates5 observed that after pretreatment with protamine sulfate there was an increase in rabbit urothelial permeability, both in vivo and in vitro, to water, urea, and calcium. This effect was reversed with pentosanpolysulfate (PPS). They concluded that the protamine sulfate affected the GAG layer, and that this was repaired by PPS. However no microscopic evidence of the anatomical changes were presented in this paper. This study was confirmed by Nickel and colleagues,6 who compared PPS and heparin and Future of Bladder Control hyaluronic acid as treatment groups. The authors concluded that heparin was the best of the three agents in efficacy, but pointed out that this may be due to its anti-inflammatory prop- not alter the ability of protamine to increase the urothelial permeability.11 This implies that the protamine does not act at the level of the GAG layer but rather at the level of the luminal In the near future we foresee the novel intravesical vanilloid therapies, capsaicin and resiniferatoxin, as challenging the concept of how we treat OAB. erties. Others have suggested that the primary role of the GAG layer may be more in line with an antibacterial adherence function, as outlined by Hanno and associates.7 The GAG layer may also be important for the formation and attachment of particulates to the urothelium and stone formation.8,9 However, there are several problems with the theory of the GAG layer being the primary urothelial plasma barrier. The first is that protamine sulfate can be used as a cytodestructive agent.10 Second, the GAG layer does not prevent small molecules such as amiloride from reaching, and subsequently interfering with, the sodium channels expressed on the surface of the umbrella cells. Third, the polyene antibiotic nystatin can reach the urothelium, as evidenced by increases in the short-circuit currents and reduction in transepithelial resistance to insignificant values as it generates nonspecific cation pores in the cholesterol-containing luminal membrane of the umbrella cells. Fourth, using microelectrodes, the first resistive barrier found is upon entry into the cell. Fifth, addition of monomeric arginine or polyvalent cations does not alter transepithelial ion permeability based on electrical measurements. Sixth, use of hydrolytic agents such as neurominidase, hyaluronidase, or chondroitonase, or proteolytic agents such as trypsin or kallikrein (to deliberately strip the urothelium of the GAG layer) does umbrella cells. Regardless, one cannot discount the possibility that under certain conditions the GAG layer may play a supportive role in barrier function. Indeed, the most parsimonious explanation that takes into account all of the aforementioned data is that the primary barrier function of the urothelium resides within the luminal cells of the urothelium, and that an intact GAG layer may be able to “plug the holes” if the primary barrier is weakened but not thoroughly destroyed. The Umbrella Cells These large, luminal cells are the primary urine-plasma barrier. They are unique in several ways. First, they are the largest epithelial cells in the terms of water, urea, potassium concentrations and osmolality, and pH. Umbrella cells are so called for their shape, as they look like umbrellas over the intermediate cell layer; they may cover several intermediate cells and have a stem that may extend to the lamina propria of the urothelium. They are capable of changing shape and can increase their luminal surface area as the bladder fills, and conversely decrease their luminal surface area as the bladder empties. How this phenomenon occurs is still under debate. The prevailing theory at the present time is that there is a large number of discoidal vesicles with asymmetric membrane structures located just beneath the apical membrane. These vesicles decrease in number with bladder stretch and increase the electrical capacitance of the luminal surface of the umbrella cells. This is consistent with the notion of exocytosis of these vesicles to create additional surface area.13 Conversely, the discoidal vesicles may be infoldings of membrane that stretch out and disappear with the requirement for increased surface area.14 These discoidal vesicles are Very high serum levels of oxybutynin can be achieved with minimal systemic side effects. body. Second, they have the ability to increase and decrease their surface area considerably, primarily at the apical (luminal) surface. Third, they may be multinucleated. Fourth, they have a very unusual apical surface membrane, which is described as asymmetric unit membrane with the outer leaflet consisting of protein plaques (composed of a unique protein, uroplakin12) and lipid, with a primarily lipid inner leaflet. Fifth, these cells allow maintenance of an extremely high gradient between the plasma and urine in associated with a dense network of filaments,15 which may be connected to the uroplakin plaques.16 In addition to the uroplakin armor of the apical membrane, a girdle of tight junction connections to neighboring umbrella cells, known as the zonula occludens, provides the cellto-cell contacts that make the umbrella cell layer a continuous sheet of impermeable barrier.17 While the GAG layer may play a secondary, supportive role in barrier function under certain conditions, it seems VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY 3 Future of Bladder Control continued Figure 2. The role of the intestinal epithelium in the absorption and metabolism of orally administered drugs. Mouth Intestinal Epithelium Liver Dirctly absorbed Metabolized by P450 3A4 CYP Effluxed by P-glycoprotein side effects. How can this be? How can intravesical instillation of oxybutynin be so different from the conventional oral administration of the immediate release (3 times a day) oxybutynin? We have been puzzled by this apparent paradox for over 10 years. In the sidebar we reveal the secrets to understanding this paradox. If constant, therapeutic levels of 4 VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY Drug Absorption and Metabolism We have all been taught that when you take a pill, the drug is absorbed through the gastrointestinal tract and metabolized by the liver. The first-pass effect determines the amount of metabolites in the body. However, studies addressing drug metabolism have found a more complex and interesting processing of oral drugs.18 When you swallow a drug, four things can occur (Figure 2): 1) the drug can be directly transported to the vein unaltered and be later metabolized by the liver; 2) the drug can be directly metabolized by the cells of the proximal gut, with no further action by the liver; 3) the drug can be metabolized both by the proximal gut and the liver; and 4) the drug can be unabsorbed or processed back into the gut lumen. Recent studies19 have demonstrated that oxybutynin is metabolized not only in the liver but also in the proximal small intestine (but not in the large intestine). There is evidence that the parent compound, oxybutynin, and its metabolite, desethyloxybutynin, have similar effects on bladder smooth muscle but differ significantly with regard to their effects on the salivary gland, the parent compound not causing as much dry mouth as the metabolite. Interestingly, with oxybutynin XL's Let’s restate the oxybutynin paradox. • First, why can you deliver ten times higher levels of oxybutynin intravesically and see almost no systemic side effects? • Second, why does the new controlledrelease oral oxybutynin have significantly fewer side effects than conventional, immediate-release oral oxybutynin, when they are the same drug? The development of the new controlledrelease oral oxybutynin (oxybutynin XL) has led us to realize that the answer is probably that the majority of the effects on the salivary gland are produced by the oxybutynin metabolite desethyloxybutynin, which is produced not only by first-pass metabolism in the liver but also by direct cytochrome P450 metabolism in the gut wall. With oxybutynin XL, the drug is delivered at a steady rate for 24 hours, spending only 3 to 5 hours in the upper gut. Therefore gut wall metabolism and first-pass metabolism in the liver are proportionally reduced, and subsequently one finds a reduced ratio of metabolite to parent compound systemically. This means one can achieve greater efficacy on the bladder with less dry mouth (Figure 3). Small Bowel There are over a dozen peer review articles reporting successes of intravesical anticholinergic drug treatment for overactive bladder and detrusor hyperreflexia. Why, then, is intravesical anticholinergic drug treatment not widely used? The reason is that this method of delivery is just too cumbersome, as it requires repeated manipulation (bladder catheterization 3 to 4 times a day) of the lower urinary tract. Unless one is considering a patient already on clean intermittent selfcatheterization, most patients will not accept this complex form of therapy. There is one other amazing piece of information that can be gathered from a metaanalysis of the published literature on intravesical anticholinergic therapy, and that is that very high serum levels of oxybutynin can be achieved with minimal systemic The Oxybutynin Paradox Metabolite Liver Parent or Bloodstream Small Bowel Intravesical Drug Delivery oxybutynin in the bladder can be achieved without repeated instrumentation, this would provide an extremely effective regimen to control OAB. The key to this intravesical regimen is a long-lasting intravesical pump to deliver the desired drug dose. This technology is not available today but is currently under development. We will discuss two examples in the following sections. Drugs to treat bladder spasms, pain, and even bladder cancer may all be delivered by this intravesical pump technology. Liver Metabolite Large Bowel clear that primary barrier function of the urothelium resides in the unique specializations of the umbrella cells. Direct Absorption Parent Figure 3. Differences in absorption and metabolism of normal (top) and controlled-release (bottom) oxybutynin. Based on the above discussion and work referenced, we are most excited about the prospect of transcutaneous anticholinergic drug delivery. It is only logical that transcutaneous application of anticholinergic drugs can further decrease side effects while still maintaining efficacy. If once- or twice-a-week transcutaneous anticholinergic patches can be developed, then higher-dose regimens as well as increased patient compliance can be expected. Future of Bladder Control controlled release technology, there is significantly less metabolite versus the parent compound—a desirable combination, but how is it achieved? (See sidebar 1.) Alternative Bladder Drug Delivery Intravesical administration of traditional drugs has been tried as an alternative to conventional oral administration for the unstable bladder. This route of installation offers the possibility of obtaining a high concentration of drug at the target organ while avoiding systemic side effects. In the properly motivated patient, or patients who cannot tolerate oral anticholinergic agents, intravesical installation should be considered as a nonsurgical option. Agents studied thus far include emepronium bromide, intravesical lidocaine, oxybutynin, and verapamil. The Bladder Pump Intravesical therapy of anticholinergic drugs is effective, but this method of delivery is just too cumbersome for most patients, as it requires repeated manipulation of the lower urinary tract. However, if constant therapeutic levels of oxybutynin in the bladder without repeated instrumentation could be achieved, this would provide an extremely effective regimen to treat OAB. The key to this intravesical regimen is a long-lasting intravesical Figure 4. The UROSTM bladder pump is currently under development. pump to deliver the desired drug dose. This technology, called UROS, is currently under development by Situs Corporation (San Diego, CA). The concept involves a reservoir that can be easily inserted into the bladder and filled with the desired drug. The reservoir size must be balanced so that it is not too small to be voided out yet not too large to cause bladder irritation or obstruction (Figure 4). The reservoir will be able to constantly release a precise drug quantity into the bladder. When the reservoir is empty, for example after 30 days, a flexible cystoscopy can be used to retrieve the empty reservoir and a new reservoir can be inserted. Drugs to treat bladder spasms, pain, and even bladder cancer may all be delivered by this technology in the future. Initial experience with the bladder pump was presented at the 95th Figure 5. The predominant A-delta afferent contribution to the normal micturition reflex. Cerebral Cortex Cerebral Cortex (+ -) Brain Stem (+ -) Brain Stem X Sustained Bladder Drug Release Singh and associates20 have developed an intravesical, fibrinogen-based, sustained-retention drug delivery system. This technology, termed therapeutic adhesive (TA), was developed for application to resected tumor beds to reduce local tumor recurrences. They evaluated the feasibility, safety, and retention of the TA, formulated with 5-fluorouracil (5-FU TA), after intravesical application in a mouse model. Radiolabeled [14C]5-FU TA or [14C]5-FU solution was delivered intravesically in this manner to C3H/He female mice. Figure 6. The switch in afferent contribution to the micturition reflex from A-delta predominant to C-fiber predominant following spinal cord transection or after the development of inflammatory disease. Note that capsaicin and other vallinoids can block the C-fiber contribution under these conditions. Spinal Tract Spinal Tract Myelinated A-delta Afferents Unmyelinated C Afferents Ganglion Bladder Myelinated A-delta Afferents Capsaicin Block Capsaicin Block Spinal Efferents Annual American Urological Association Meeting in Atlanta in 2000. Findings presented at the AUA meeting focused on two clinical studies involving a total of 16 women. In the first (randomized and blinded) study, 13 healthy females received saline via the UROS infusor for three days. Results showed they tolerated the device well and voided normally. In the second trial, three women suffering from overactive bladder were treated with oxybutynin solution using the infusor for 24 hours. The results of the latter trial revealed that two patients experienced a greater than 100% increase in bladder capacity and all three had acceptable tolerance levels and no side effects. Spinal Efferents Unmyelinated C Afferents Bladder Ganglion VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY 5 Future of Bladder Control continued After drug administration, retention of 14C in the bladder was quantified by storage-phosphor autoradiography. A 2.6-fold increase in retention was observed with 5-FU TA when compared with 5-FU solution. The AUC (2 min-5 h) for 5-FU TA was 685 nmol h/mm2, compared with 260 nmol h/mm3 for 5-FU solution. No signs of toxicity in the bladder tissue or treatment-associated adverse unmyelinated C-fiber afferents, whereas in intact cats it consists of myelinated A-delta afferents.21 This was demonstrated with electrophysiological recording and also by the administration of capsaicin, a neurotoxin that is known to disrupt the function of C-fiber afferents.22 In normal cats, capsaicin injected systemically in large doses (20–45 mg/kg, s.c.) did not block reflex contractions Why not use the bladder as a privileged site for systemic delivery of fragile drugs that cannot escape digestion and degradation of the gastrointestinal tract? effects were observed in the mice. The lesson from this study is that clever methods can be developed to achieve safe and effective longerterm intravesical delivery for bladder and even systemic conditions. Why not use the bladder as a privileged site for systemic delivery of fragile drugs that cannot escape digestion and degradation of the gastrointestinal tract? If the drug can pass across the urothelium, we may be able to achieve surprising systemic delivery amounts and durations. Moreover, we can easily imagine that sustained intravesical drug release for several hours or a few days would be ideal therapy for urinary tract infections. Intravesical Peppers The central pathways controlling bladder function are organized as simple on-off switching circuits that maintain a reciprocal relationship between the bladder and external urethral sphincter. The principal reflex components of these switching circuits are illustrated in Figure 5. Micturition reflexes among normal and chronic-spinal-injured animals are markedly different. In chronicspinal-injured cats, the afferent limb of the micturition reflex consists of 6 VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY of the bladder or the A-delta fiberevoked bladder reflex. However, in chronic-spinal-injured cats, capsaicin (20–30 mg/kg, s.c.) completely blocked rhythmic bladder contractions induced by bladder distension and the C-fiber-evoked long latency reflex firing recorded from bladder postganglionic nerves. Thus there seems to be a considerable reorganization of reflex connections in the spinal cord of the cat following the interruption of descending pathways from the brain (Figure 6). The normal sensations of bladder filling appear to be mediated by small myelinated A-delta fibers. In the cat, A-delta fibers have pressure thresholds in the range of those at which humans report the first sensation of bladder filling.23 However, C-fiber afferents, which are small and unmyelinated, have very high mechanical thresholds and do not respond to even high levels of intravesical pressure in the cat.24 Nevertheless, they are activated by noxious chemical irritation24 or by cold.25 Furthermore, in the irritated state, these fibers become responsive to low-pressure bladder distension like mechanoreceptive A-delta fibers. Cfibers, therefore, are normally “silent” and appear to have a specific function, that is, signaling of inflammatory or noxious events in the bladder.26 The vanilloids, capsaicin and resiniferatoxin, activate nociceptive sensory nerve fibers through an ion channel recently discovered by Caterina and associates27 and known as vanilloid receptor subtype 1 (VR1). This receptor is a nonselective cation channel and is activated by increases in temperature to within the noxious range and by protons, suggesting that it functions as a transducer of painful thermal stimuli and acidity in vivo. When activated, the channel opens, allowing an influx of calcium and sodium ions that depolarizes the nociceptive afferent terminals, initiating a nerve impulse that travels through the dorsal root ganglion into the central nervous system. Noxious temperature uses the same elements, which explains why the mouth feels hot when eating chili peppers.28 Previously called the capsaicin receptor, VR1 has been localized in the spinal cord, dorsal root ganglia, and visceral organs, including the bladder, urethra, and colon. Activation of VR1 results in spikelike currents29 that selectively excite and subsequently desensitize Cfibers. Capsaicin desensitization is defined as long-lasting, reversible suppression of sensory neuron activity.30 How fast and for how long the desensitization develops is related to the dose and time of exposure to capsaicin, and the interval between consecutive dosing.31,32 The transient increase in intracellular concentration of calcium ions also leads to activation of intracellular enzymes, peptide transmitter release, and neuronal degeneration.33,34 Intravesical Capsaicin Recently, capsaicin, the “gold standard” in the vanilloid class of drugs, has been tried as an intravesical drug, Future of Bladder Control with limited success. If OAB is due to sensitization and/or recruitment of C-fibers resulting in an overall increase in the C-fiber contribution to mechano-reception, then functional desensitization of C-fiber afferent neurons may decrease detrusor instability. However, capsaicin causes initial stimulation of the unmyelinated C-fibers, resulting in severe discomfort or pain along with release of the neurotransmitters substance P and/or neurokinin A in the bladder. The use of capsaicin is still largely experimental, and includes patients with detrusor hyperreflexia; however, some trials are ongoing with the use of capsaicin for detrusor instability, especially when the patient has failed other forms of treatment. In a recent capsaicin study of detrusor hyperreflexia, 44% of patients had satisfactory continence, 36% were improved, and only 20% failed treatment.35 Clinical results of intravesical capsaicin. Detailed descriptions of the key clinical report of intravesical capsaicin for treatment of detrusor hyperreflexia can be seen in a recently published article by Chancellor and de Groat.26 Most of the clinical studies report that intravesical capsaicin achieved over 60% urodynamic improvement 1–2 months after capsaicin instillation. The maximum cystometric capacity increased from 27% to 220%. The effect of capsaicin on clinical and urodynamic parameters was long lasting, exceeding one year in some patients. In a meta-analysis of the six series on a total of 131 patients, mean pretreatment bladder capacity was 144ml (range, 72mL–195 mL). The mean postcapsaicin cystometric capacity, although at different time points, was 267 mL (range, 185 mL–321 mL). Mean symptomatic improvement was 72% (range, 40% to 100%). Wiart and colleagues36 reported on 12 paraplegic patients treated either with 1mM capsaicin in 30% alcohol or placebo (30% alcohol alone). One hundred mL of either capsaicin or alcohol placebo was instilled for 30 minutes using outpatient procedures without anesthesia. Urodynamic studies and bladder diaries were compared before therapy and 30 days later. All of the capsaicin patients reported clinical improvement with significant regression of urine leakage episodes (P = .002), and sensory urgency (P = .01). Only one placebo subject had subjective improvement. This double-blind, placebo-controlled trial confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. Intravesical Resiniferatoxin Resiniferatoxin (RTX) is a much more potent sensory antagonist than capsaicin. It is approximately a thousand times “hotter” than capsaicin, based on the Scoville Heat Scale.37 Like capsaicin, it possesses vanilloid receptor agonist activity, resulting in desensitization, but RTX acts without the potent neuronal excitatory effect of capsaicin and therefore elicits less discomfort. The use of this vanilloid promises an alternative to capsaicin that would be potentially therapeutic for OAB and detrusor hyperreflexia. However, formal controlled trials still have to be performed to determine the precise use and dosage for this agent. The key advantage of RTX is that it is at least as effective as capsaicin, without much of the local side effects, such as pain and inflammatory neuropeptide release. RTX is the principal active ingredient in the classic drug euphorbium, the air-dried latex (resin) of the cactus-like plant Euphorbia resinifera, Berg.38 In 1989, RTX was recognized as an ultrapotent analogue of capsaicin.39 At the same time, howev- Speculation on Prevention of Detrusor-Sphincter Dyssyergia in Spinal Cord Injury (SCI) Patients with Intravesical RTX One of the most important priorities in SCI research is early therapy to prevent, and even cure, the sequelae of SCI. Although there has been significant progress in early systemic treatment, such as antiinflammatory steroid administration to minimize the size and severity of spinal cord damage, there has never been an investigation of early urologic intervention to prevent and minimize life-long urologic complications. We have recently observed that intravesical RTX treatment results in a reduction in the bladder-spinal cord-sphincter response in both normal and SCI animals, resulting in the latter case in a reduction/elimination in detrusor-sphincter dyssynergia (DSD; Figure 7). In addition, we have seen a reduction or elimination of detrusor hyperreflexia (DH) and micturition bladder pressure following acute neuromuscular blockade in chronic SCI animals.48 It seems, therefore, reasonable to suggest that early treatment with intravesical RTX during the spinal shock phase may reduce or prevent the development of DH and autonomic dysreflexia by prophylactic elimination of DSD. Additional indirect evidence in support of this notion can be seen in a study in which urinary diversion at the time of SCI, which sidestepped the deleterious effects of DSD, prevented the hypertrophy of the bladder and bladder afferent neurons.49 If prophylactic intravesical RTX treatments do, in fact, prevent much of the lower urinary tract dysfunction seen in SCI patients, then the need for many surgical and other drug treatments, with their significant side effects, becomes eliminated. Figure 7. The effects of intravesical resiniferatoxin (RTX) in 10% EtOH/saline administered in graded doses on bladder and external urethral activity were assessed during continuous cystometry in urethane-anesthetized female SD rats with chronic spinal cord injury. EUS electromyography revealed a dose-dependent decrease in detrusor-sphincter dyssyergia with RTX (P < .0001 by Repeated Measures ANOVA; P < .03, 0 vs 1000 nM RTX by paired t test), even in the face of a concordant increase in bladder contraction amplitude (P < .05, 0 vs 1000 nM RTX by paired t test; data not shown). VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY 7 Future of Bladder Control continued er, it was also realized that although RTX mimics most capsaicin actions, it also has unique pharmacological effects,40 such as the desensitization without prior excitation of the pulmonary chemoreflex pathway.41 The mechanisms underlying the differences between RTX and capacity increasing from 50% to 900% of pretreatment measures. Lazzeri and colleagues46 reported using intravesical RTX (10 nM) in eight normal patients and seven patients with overactive bladders. In normal subjects, RTX did not decrease the volume required to elicit the first desire to void and did Resiniferatoxin has also been reported to be helpful in patients who did not improve after capsaicin. Resiniferatoxin Clinical: A Better Bladder Pepper? Cruz and associates44,45 instilled 50 nM–100 nM RTX, dissolved in 100 mL solution of 10% alcohol, for 30 minutes in seven neurologically impaired patients with detrusor hyperreflexia. Itching or mild discomfort were the only symptoms evoked in four patients during the first minutes of the treatment. In five of the seven patients, urinary frequency decreased by 33% to 58%, and this effect was detected as soon as the first day after treatment. Three patients, who prior to treatment were incontinent, became dry most days following treatment. Improvement was sustained for up to 3 months. Four patients had urodynamic improvement with a rise in maximum cystometric 8 VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY not produce warm or burning sensations at the suprapubic or urethral level during infusion. However, in patients with overactive bladder, mean capacity increased from 175 ± 36 to 281 ± 93 mL (P < .01) immediately after instillation, but was not significantly increased after four weeks (217 ± 87 mL). RTX has also been reported to be helpful in patients who did not improve after capsaicin. Lazzeri and colleagues47 presented data on 9 SCI patients with detrusor hyperreflexia treated with RTX. These patients were reported to have failed intravesical Spinal Cord capsaicin actions are just beginning to be understood. RTX induces slowly activating, persistent currents in dorsal root ganglion neurons as measured under patch-clamp conditions.29,42,43 These sustained currents prefer desensitization to excitation (the change in membrane potential is not sufficient to cause action potential formation, although the rising intracellular calcium levels can activate biochemical pathways leading to desensitization), which is in accord with the general pharmacological profile of RTX. capsaicin therapy. All nine patients received 30 mL of 10 M RTX for 30 minutes. Fifteen days after RTX, mean cystometric capacity significantly increased from 188 ± 21 mL to 399 ± 120 mL (P < .01), and remained increased four weeks later (402 ± 71 mL, P < .01). A recently completed North American multicenter RTX clinical trial was designed as a prospective, dose-escalating, single-blind, placebo-controlled study comparing the effects of seven concentrations of RTX (0.005, 0.025, 0.05, 0.1, 0.2, 0.5, 1.0 (M of RTX 10% ethanol in saline) and placebo (10% ethanol) for treatment of neurogenic bladder. Each patient received a single dose.50 Safety, tolerance, and bladder function assessments were made at screen, immediately following dosing, and at weeks 1, 3, 6, and 12, and quarterly thereafter until a return to baseline bladder function was obtained. The final analysis of the results of this study is being compiled and a few trends can be seen. First, there were no significant differences between control and RTX at the low- HSV-Gene Transport HSV-Gene Injection Figure 8. The use of human simplex virus as a vector for directed transfection of afferent nerves that innervate the urinary bladder. Such an approach has great potential for the treatment of bladder dysfunction. Future of Bladder Control est doses of 0.005 M to 0.01 M. Second, in patients with decreased bladder capacity, the mean change in cystometric capacity was markedly greater than for the placebo dose group. Third, the mean number of incontinence episodes from pretreatment of patients treated with 0.05 M, 0.5 M, and 1.0 M decreased by 1 to 2 fewer episodes compared to placebo. Adverse events considered to be related to RTX were generally mild to moderate and transient. One patient discontinued from the study due to autonomic dysreflexia. In a patient population involving many SCI patients, the occurrence of AD is an expected event, especially during urologic studies. Cystoscopic evaluation revealed no adverse treatment effect due to RTX. No signs of areflexia or urinary retention were noted. Clinically significant changes in laboratory abnormalities did not occur. RTX for Interstitial Cystitis Interstitial cystitis (IC) represents a diagnostic and therapeutic challenge to almost all urologists. Traditional pharmacological approaches involve the use of anticholinergics, antidepressants, muscle relaxants, antispasmodics, calcium channel blockers, antihistamines, and analgesic medications. Intravesical agents in the form of dimethyl sulfoxide (DMSO), oxychlorosene sodium, heparin, lidocaine, bicarbonate, and hydrocortisone have been used for some time. Bacille Calmette-Guerin and hyaluronic acid have been more recently employed. Relief of the symptoms (of pain and frequency) is minimally achieved, if at all. Sacral nerve stimulation and surgery are used after all conservative therapies have failed. At present, novel approaches using topical agents such as capsaicin and resiniferatoxin are being explored. Lazzeri and associates51 recently presented prospective randomized results of intravesical RTX in IC patients from Italy. In 18 patients with bladder hypersensitivity, there While traditional medicine treats symptoms, gene therapy addresses the deficiency that causes the symptoms. With improved understanding of the human genome and evolving techniques to construct gene therapy vectors that manipulate our genetics, the way we practice medicine will be forever changed (Figure 8). Drug delivery technologies will allow us to get the drug or a gene to a specific target organ and thus limit systemic side effects. The bladder is very accessible to these therapies. Through gene therapy we can replace, supplement, or suppress a We believe that there is a way to prevent the inevitable deterioration of diabetic cystopathy through organ-specific gene therapy. was a significant improvement in urinary frequency over 24 hours, nocturia, and pain scale recording with RTX (10 nM) versus placebo (saline) treatment patients after 30 days, and partial persistent effect after 90 days. We feel it should be a priority to study intravesical RTX in IC patients in an FDA-approved protocol in the United States. The Next Big Thing Real excitement lies just around the corner. We believe that the field of urology, along with all specialties of medicine, is on the brink of a revolution called molecular medicine. protein or cytokine to correct a disease process. Gene therapy in urology may not be that far away. For example, many diabetics will develop a sensory neurogenic bladder (diabetic cystopathy) within 10 years of disease onset. The symptoms are progressive and include decreasing bladder sensation and increasing bladder capacity. The end result is a large and acontractile bladder that is treated by catheterization or urinary diversion. There are no medical treatment options for diabetic sensory neuropathy. We believe that there is a way to prevent the inevitable deterioration of diabetic cystopathy through Main Points • The aging population will lead to an increase in urinary incontinence and overactive bladder problems. • Intravesical pumps currently under development will provide nonsurgical options for patients. • Trials have confirmed the efficacy of intravesical capsaicin for detrusor hyperreflexia. • Resiniferatoxin (RTX) is as effective as capsaicin, but without side effects such as pain and inflammatory neuropeptide release. • RTX treatment may eliminate the need for surgical and other drug treatments of lower urinary tract dysfunction in patients with spinal cord injuries. • Gene therapy is likely to revolutionize urology in the near future. VOL. 4 NO. 1 2002 REVIEWS IN UROLOGY 9 Future of Bladder Control continued organ-specific gene therapy. In a rat model of diabetic cystopathy, the bladder wall is injected with a specially constructed nonreplicating human simplex virus (HSV) vector. This recombinant herpes vector mediates expression of ß-nerve growth factor ßNGF), a neurotrophic factor that in experiment conditions has been shown to prevent and reverse diabetic neuropathy. Using the safe, nonreplicating, latent HSV vector, expression of ß-NGF occurs not only in the bladder but also in the dorsal root ganglion of the pelvic nerve. We have exciting data suggesting that overexpression of ß-NGF in the bladder and dorsal root ganglia can decrease diabetic cystopathy.52 All of this animal work is obviously very preliminary. However, we hope readers will gain insight into the potential that this type of research offers. In the future, we imagine patients coming into the cystoscopy suite of an urologist for cystoscopic-based gene therapy. A man with BPH will have the gene for the expression of a prostate apoptosis factor injected into his prostate instead of a formal resection. A woman with diabetes will have NGF vectors injected into her bladder. And finally, a man with impotence will have an injection of genes such as vascular endothelial growth factor (VEGF) or nitric oxide synthase (NOS) injected into his penis to promote normal erectile function. This form of treatment will not be available today or tomorrow, but—who knows?—perhaps it is not as far away as it once seemed. cholinergics. In addition, intravesical resiniferatoxin promises target-specific and long-lasting therapy in the near future. We have also speculated about the farther horizon of molecular medicine, through which gene therapy may radically alter medical paradigms. 10 VOL. 4 NO. 1 2002 18. 19. References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. Conclusion There is a revolution starting in urology. 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