SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

Botulinum toxins (BoNTs) are known for their ability to potently and selectively modulate neurotransmission for successful long-term treatment of muscle hypercontractility. Recent studies suggest that BoNT has effects on modulation of sensory processing, inflammation and glandular function. Urologists and urogynaecologists have become interested in the potential application of BoNTs in patients with lower urinary tract symptoms, including detrusor and sphincter overactivity, bladder hypersensitivity, interstitial cystitis/painful bladder symptoms and benign prostatic hyperplasia. We review the biological action of BoNT in bladder and prostate, and present the techniques and results of the clinical studies with BoNT in the lower urinary tract.


Abbreviations
BoNT

botulinum neurotoxin

SCI

spinal-cord injury

DSD

detrusor-sphincter dyssynergia

(I)(N)DO

(idiopathic) (neurogenic) detrusor overactivity

OAB

overactive bladder

SNARE

soluble N-ethylmaleimide-sensitive fusion attachment protein receptor

NGF

nerve growth factor

COX

cyclooxygenase

IC/BPS

interstitial cystitis/bladder pain bladder syndrome

MCC

maximum cystometric capacity

CIC

clean intermittent catheterization

PVR

postvoid residual volume

DMSO

dimethyl sulphoxide.

A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

BoNT, produced by Clostridium botulinum, a Gram-positive, rod-shaped anaerobic bacterium, was originally thought to only act by inhibiting acetylcholine release at the presynaptic cholinergic neuromuscular junction, and has been used effectively for different conditions with muscular hypercontraction [1,2]. There are seven immunologically distinct neurotoxins designated as types A–G [1–3]. All serotypes block transmission at neuromuscular junctions to varying degrees, but the effects of BoNT-A are the most prolonged, and this serotype has been the most extensively studied, mainly in models of neurotransmission in striated muscle.

Only BoNT-A and BoNT-B are in clinical use; there are several available BoNTs, including onaBoNT-A (Botox; Allergan, Inc., Irvine, CA, USA) and aboBoNT-nA (Dysport, Ipsen Ltd, Berkshire, UK), and RimaBoNT-B (Myobloc, Elan Pharmaceuticals, Inc., Princeton, NJ, USA). The potency of each toxin is expressed in units of activity. Although there are similarities among the commercial preparations of BoNT, they have different doses, efficacy and safety profiles, and should not be considered generic equivalents comparable by single-dose ratios [3].

The application of BoNT for the treatment of LUTS was initiated in the late 1980s. Dykstra et al.[4] described the injection of BoNT into the external urethral sphincter in patients with spinal-cord injury (SCI) to induce chemical sphincterotomy and to lower detrusor-sphincter dyssynergia (DSD). A resurgence of interest in BoNT was led by Schurch et al.[5], who reported the successful treatment of patients with SCI and neurogenic detrusor overactivity (NDO). Maria et al.[6] reported the therapeutic effects of BoNT in patients with BPH. As the uses of BoNT continue to expand in urology, it is important to understand the mechanism and clinical effects by which the toxin works on different tissue types and disease entities.

HOW BoNT WORKS

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

BoNT-A is initially synthesized as an inactive chain of 1285 amino acids, and is activated when the single chain is cleaved by an endogenous Clostridial protease [1,7]. This creates a di-chain polypeptide containing a 50-kDa light chain and a 100-kDa heavy chain linked covalently by a single disulphide bond [7]. BoNT-A inhibits signal transmission at the neuromuscular and neuroglandular junction in four discrete stages: (i) binding of the toxin heavy chain to a specific nerve terminal receptor; (ii) internalization of the toxin within the nerve terminal; (iii) translocation of the light-chain into the cytosol; and (iv) inhibition of neurotransmitter release.

BoNT-A recognizes and enters neurones by binding to the synaptic vesicle protein SV2 during neurotransmitter exocytosis when more active receptors are exposed [8]. BoNT-A attaches itself to receptors located on the nerve terminal via its heavy-chain binding domain, then BoNT-A is taken up in a neurone activity-dependent manner by using SV2 as its protein receptor and attacking active neurones in a receptor-mediated endocytotic process. After the process of internalization, the heavy chain is instrumental and creates ion channels or pores in the vesicle wall, and the light chain is translocated into the cytosol.

In nerve terminals, synaptic vesicles fuse with the presynaptic membrane where they release the neurotransmitter into the neuromuscular or neuroglandular junction. Vesicle fusion is mediated by a set of ‘soluble N-ethylmaleimide-sensitive fusion attachment protein receptor’ (SNARE) proteins. In nerve terminals affected by BoNT, light-chain proteolytic fragments are released into the cytosol and cleave specific peptide bonds present in the synaptic fusion complex, and prevent exocytosis of neurotransmitter-containing vesicles at the nerve terminal [1,2,9]. Each botulinum serotype cleaves a distinct protein site; BoNT-A cleaves synaptosomal-associated protein (SNAP-25), and type B cleaves synaptobrevin [1,2].

HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

The varying periods that each toxin effectively inhibits exocytosis depends on the differences in SNARE-binding profiles between the BoNT serotypes. BoNT-A, when used clinically for the treatment of dystonia, has by far the longest duration of activity, inducing clinical effects on neuromuscular activity for >4 months, compared with a duration of effect of ≈2 months for BoNT-B or <4 weeks for BoNT-E [2,3]. Recovery of neurotransmission depends on the removal of the BoNT protease as well as the restoration of intact SNARE proteins. In addition, structural differences in the end organs will lead to a different duration of effects even with the same toxin. In the following sections we discuss the sustained duration of clinical efficacy of >6 months reported with urological BoNT applications.

RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

BoNT has effects on the motor function, sensory function, glandular function, and anti-inflammation through the modulation of various neurotransmitters release in different kinds of tissue.

Motor effects: Smith et al.[10] found significant decreases in the release of labelled acetylcholine in normal rat bladders injected with BoNT-A, suggesting that BoNT-A could reduce cholinergic nerve-induced bladder activity. In addition, the release of other transmitters can be inhibited, particularly if high enough concentrations are used [7–11]. For example, contractile data suggest that onaBoNT-A might impair ATP release in addition to actylecholine release from isolated bladder tissue [11]. Morphological changes after onaBoNT-A injection include subsequent compensatory nerve sprouting and the creation of extra-junctional synapses [12]. The sprouts are retracted and endplate functioning returns to normal when exocytosis at the parent terminal eventually recovers [12].

Studies have shown that onaBoNT-A produces no persistent changes in muscle fibre internal architecture after recovery from paralysis. In the study of structural change in detrusor muscle, Haferkamp et al.[13] collected 30 biopsies from 24 patients with a diagnosis of neurogenic overactive bladder. They observed no significant changes in muscle cell fascicles, intercellular collagen content or muscle cell degeneration when comparing biopsies taken before and 3 months after BoNT-A administration. Unlike striated muscle, axonal sprouting in detrusor smooth muscle was limited following onaBoNT-A administration. In another study, bladder wall specimens obtained at cystectomy in 45 patients with neurogenic overactive bladders showed that patients who had received an injection with onaBoNT-A had significantly less fibrosis of the bladder wall than those who had not received the injection. In addition, there was a trend that responders to the toxin therapy had less fibrosis and oedema of the bladder wall than nonresponders [14]. Apostolidis et al.[15] reported that BoNT injections do not produce significant inflammatory changes, fibrosis, or dysplastic changes in human bladder urothelium/suburothelium after one injection, nor in a few repeat treatment biopsies in patients with NDO or idiopathic DO (IDO).

Sensory effects: There has been increasing evidence to support that BoNT might also inhibit afferent neurotransmission and have analgesic properties [16]. Changes in afferent activity might influence pain through both direct sensory effects and indirect central reorganization in the CNS. It has been shown that onaBoNT-A inhibits the release of calcitonin gene-related peptide, substance P, glutamate, nerve growth factor (NGF) and ATP, which are mediators of painful sensation. Furthermore, in vivo animal studies also support a role for onaBoNT-A in relieving nociceptive pain. In a model of somatic pain associated with formalin-induced inflammation, rats pretreated with BoNT-A had significantly reduced pain behaviour and glutamate release from 5 h to 12 days after the injection [17]. Similar effects were observed in an acetic acid-induced bladder pain model [18].

Bladder urothelium is important in the sensory transduction mechanisms modulating micturition, particularly in conditions of increased sensory nerve transmission after chronic inflammation and SCI [19]. OnaBoNT-A was shown to inhibit ATP release from the urothelium in SCI rat bladders [20]. The effects of BoNT are not limited solely to inhibiting neurotransmitter release. For example, studies have shown that TRPV1 (i.e. capsaicin-sensitive) receptors are released by SNARE-dependent processes and can be inhibited by onaBoNT-A treatment, during laboratory studies [21]. Giannantoni et al.[22] reported that intravesical onaBoNT-A injection reduced the NGF content in the bladder tissue of patients with NDO. The reduction in NGF content leads to a decrease in the hyperexcitability of C-fibre bladder afferents, thereby reducing NDO. Thus, the inhibitory effects of BoNT on sensory function might relieve somatic and visceral irritative symptoms.

Anti-inflammation: Using a capsaicin-induced prostatitis model in rats, the painful behavioural changes, polymorphonuclear cell accumulation, and cyclooxygenase (COX)-2 expression in the prostate gland and in the L6 ventral and dorsal horn induced by capsaicin injection were inhibited in dose-dependent fashion by BoNT [23,24]. OnaBoNT-A pretreatment could inhibit the capsaicin induced COX-2 expression from the peripheral organ to L6 spinal cord, and inhibit prostatic pain and inflammation. This finding suggests a potential clinical benefit of onaBoNT-A for the treatment of nonbacterial prostatitis. Furthermore, our recent studies also showed that intravesical onaBoNT-A administration blocked cyclophosphamide-induced bladder inflammation and hyperactivity and inhibited COX-2 and EP4 expression in the bladder and the spinal cord [25]. Taken together, these findings suggest that a potential benefit of BoNT treatment for prostate and bladder inflammatory conditions.

CLINICAL USE IN THE BLADDER

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

Patients with symptoms of NDO, IDO, overactive bladder (OAB), hypersensitive bladder or interstitial cystitis/bladder pain bladder syndrome (IC/BPS) have been treated with injections of BoNT into the bladder. Injection with 200–300 U of onaBoNT-A is the most commonly used dose for NDO, whereas 100–200 U of onaBoNT-A have been applied in treating IDO or OAB.

BoNT for NDO

Schurch et al.[5] showed that injections with onaBoNT-A at 200–300 U into the detrusor across 20–30 injection sites (10 U/mL per injection site) were effective in restoring continence and enabling a reduction or cessation of anticholinergic medication in patients with NDO. In that study, where 21 patients were enrolled, 17 of the 19 who were followed had restored continence within 6 weeks. To date, treatment of >900 patients with a neurogenic OAB with onaBoNT-A at doses primarily of 200–300 U in 20–30 injection sites has been reported. Treatment benefit is reported to last 6–12 months, with an acceptable side-effect profile [26].

Based on the findings of an earlier study, Schurch et al.[27] conducted a placebo-controlled Phase 2 study to assess the safety and efficacy of onaBoNT-A. Fifty-nine patients were enrolled in this study and received one treatment of 200 U or 300 U of onaBoNT-A, or placebo, and were followed for 24 weeks after treatment. The primary efficacy variable was incontinence episodes/day, as recorded by a patient bladder diary (7-day diary collected in the week preceding each study visit), measured before and at 2, 6, 12, 18 and 24 weeks after treatment. Urinary incontinence episodes were reduced by a mean of 50% and some patients (49%) reported no incontinence episodes during at least one of the 1-week periods after treatment. The treatment effect, in both active arms, lasted for the duration of the 24-week study.

Changes in urodynamic variables supported the effectiveness of onaBoNT-A; increased bladder capacity, as determined by maximum cystometric capacity (MCC), was consistently and significantly greater in the onaBoNT-A-treated patients through the 24 weeks after treatment. There was a consistent statistically significant superiority over placebo but the study was not designed to compare the two active doses. There were no significant safety concerns noted and no treatment-related adverse events were reported in any patients.

These studies show that onaBoNT-A is more effective than placebo for improving the symptoms of NDO, as measured by the reduction in weekly frequency of episodes of urinary incontinence. OnaBoNT-A has an acceptable safety profile when injected into the detrusor of patients with NDO. There was a sustained duration of efficacy of 6–9 months per injection and maintenance of efficacy with repeated injection of BoNT of up to 10 years, with no clinical intolerance, or loss of efficacy due to antibody formation [28,29].

BoNT for IDO

There has been a trend in the successive reports of BoNT in the bladder for using lower dosages that achieve clinical efficacy while minimizing side-effects such as urinary retention. Kessler et al.[30] treated 11 patients with IDO with detrusor injections of 300 U of onaBoNT-A, and the MCC increased from 220 to 340 mL. However, four patients needed clean intermittent catheterization (CIC) due to a large postvoid residual volume (PVR). Rajkumar et al.[31] treated 15 women with IDO by detrusor injections of 300 U onaBoNT-A, and 14 had improvements in urgency and frequency. The therapeutic effects lasted for 5–6 months. Popat et al.[32] used 200 U onaBoNT-A in 31 patients with IDO. Although there was a significant improvement in bladder capacity after treatment, 20% of the patients needed CIC. Schulte-Baukloh et al.[33] used 300 U of onaBoNT-A detrusor injections for seven women with OAB without DO. The bladder capacity increased by 20% and all patients could void with no need for CIC. In the authors’ previous study, detrusor injections of 200 U onaBoNT-A provided a 73.3% success rate in 30 patients with IDO, with a mean therapeutic duration of 5.3 months [34]. Further study using suburothelial injections at a dose of 200 U gave therapeutic results (85% success rate) as good as those achieved with 300 U onaBoNT-A in other studies [35].

We recently reported the evaluation of 100, 150 and 200 U of onaBoNT-A and found significant efficacy with only 100 U in IDO (73.3%) when compared with 200 U; however, there was a higher failure rate in NDO with 100 U [35]. Several groups also reported that 100 U of BoNT might be adequate for OAB and IDO. Werner et al.[36] treated 26 women with IDO, with a 53% success rate. Schmid et al.[37] treated 100 patients with IDO and reported an 88% success rate. There was a dose-related increase in adverse events with increasing doses of onaBoNT-A [35,38].

A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

Several randomized control trials of BoNT for OAB have been published; Ghei et al.[39] evaluated the efficacy and safety of rimaBoNT-B for treating OAB in a randomized, double-blind, placebo-controlled crossover trial. There were clinically statistically significant paired differences in the change in average voided volume, urinary frequency and episodes of incontinence between active treatment and placebo. There were similarly significant paired differences in the change in quality of life affecting five domains of the King’s Health Questionnaire. There were autonomic side-effects in four patients.

Sahai et al.[26] also reported a double-blind, placebo-controlled trial; they randomized patients to intradetrusor injections with 200 U onaBoNT-A (16) or placebo (18). There were significant increases in MCC at 4 and 12 weeks in patients treated with onaBoNT-A compared to placebo. OnaBoNT-A reduced frequency and urgency urinary incontinence episodes at 4 and 12 weeks, respectively. Urgency was reduced at 4 weeks in the onaBoNT-A group, and the PVR increased at 4 weeks but became insignificant by 12 weeks. Of these patients, six required CIC. There were significant improvements in quality of life after onaBoNT-A treatment. The extension study suggested that the beneficial effects of onaBoNT-A are maintained for ≥24 weeks [26].

Brubaker et al.[40] compared 200 U of intradetrusor onaBoNT-A vs placebo in women with refractory idiopathic urge incontinence; ≈60% of the women who received onaBoNT-A had a clinical response based on the patient Global Impression of Improvement. The median duration of the response was 373 days, significantly longer than the ≤62 days for placebo. However, in the onaBoNT-A group 43% of patients had an increased PVR and 75% of them had a UTI. Further injections were stopped after 43 patients were randomized [40]. These clinical trials provided evidence for the efficacy of BoNT on OAB, but the large PVR and UTI should be carefully monitored.

In a Phase 2 multicentre, randomized, double-blind study, 313 patients with OAB and urge urinary incontinence of eight or more episodes/week and eight or more voids/day at baseline received intradetrusor BoNT-A at 50, 100, 150, 200 or 300 U, or placebo. Symptoms were recorded using a 7-day bladder diary. The primary efficacy variable was weekly urgency episodes and the primary sample time was after 12 weeks [41]. The demographic and baseline characteristics were well-balanced across the treatment groups. There was durable and clinically meaningful efficacy for all onaBoNT-A dose groups of ≥100 U for the primary and secondary efficacy measures, including the proportion of incontinence-free patients. When the dose–response curves were analysed, doses of >150 U contributed a minimal additional or clinically relevant improvement in symptoms. This was also reflected in the health-related quality-of-life assessments [41]. There were dose-dependent changes in PVR; the use of CIC was also dose-dependent. The only adverse events significantly higher with onaBoNT-A than with placebo were UTI and urinary retention. This study showed that onaBoNT-A achieved durable efficacy in idiopathic OAB at doses of ≥100 U; doses of >150 U added little incremental benefit, particularly when balanced with the PVR-related safety variables. Phase 3 studies are currently underway globally for idiopathic OAB with onaBoNT-A.

INJECTION TECHNIQUES

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

How deep should BoNT be injected into the bladder? In a recent study using MRI for detecting the distribution of onaBoNT-A throughout the bladder wall after injecting 300 U for NDO, ≈18% of the onaBoNT-A solution was found outside the bladder dome and the remainder covered 25–33% of the bladder wall [42]. Injection into the suburothelium might avoid the potential loss of BoNT-A through detrusor injections, especially in the bladder of patients with IDO.

There is no consensus as to the technique of BoNT injection for IDO and OAB. Recent studies of BoNT injection for OAB or IDO used suburothelial delivery to potentially target the suburothelial sensory pathway rather than paralysis of DO in the treatment of OAB. However, because the bladder wall is thin, it might be difficult to differentiate suburothelium from detrusor [43]. We compared the onaBoNT-A effect on IDO among detrusor, suburothelial and bladder base injections. The results showed no significant difference between detrusor and suburothelial techniques [44].

A successful outcome was reported with BoNT injection into the trigone and bladder base [45]. The rationale for trigonal injection is that the trigone of the urinary bladder is rich in sensory fibres, but the role of trigonal sensory fibres on bladder urgency sensation and DO has not been fully explored. Although VUR might be a potential complication after BoNT in these areas, there is no evidence of it so far [29,44,46,47]. In the present authors’ personal experience over the past 10 years (H.C.K. and M.B.C.), trigonal and bladder base injections of BoNT are associated with a low incidence of urinary retention and a similar efficacy to intradetrusor injection.

The technique of suburothelial and trigonal injection

BoNT has been injected into detrusor, suburothelium or trigone to treat patients with OAB or IDO (Fig. 1A); 100 U of onaBoNT-A is usually reconstituted to 10 mL by normal saline. The volume is injected by delivering the solution to 10–20 sites (Fig. 1B). A suburothelial injection can be given using a procedure similar to the detrusor injection, except that the needle is inserted just into the suburothelial space. A ‘balloon’ formation is desired during infusion of the solution (Fig. 1C). When giving a trigonal injection the solution can be injected into several sites in the suburothelial space of the trigone and ≈0.5 cm from the bilateral ureteric orifices.

image

Figure 1. Intravesical BoNT injection: (A) The injection sites should be widely distributed of the bladder wall while injecting into the bladder body, and limited to the bladder base and trigone while injecting the trigone. (B) Detrusor injection, and (C) Suburothelial injection.

Download figure to PowerPoint

Besides delivering the injections under anaesthesia in hospital, we have found that it can be easily done transurethrally under local lidocaine anaesthesia in the outpatient clinic. A rigid or flexible injection cystoscope is inserted into the bladder and injections delivered thereafter. The bladder volume is typically kept at 150–200 mL and blood vessels are avoided during injection. The first observable change is in urgency, frequency and incontinence after 4–7 days, and all variables improve significantly after 4 weeks [48].

ADVERSE EVENTS OF BoNT

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

The main adverse events of intravesical BoNT injection are incomplete bladder emptying and UTIs, reported to occur in 20–43% of treated patients [26,33,35,40,44]. UTI is usually associated with a large PVR [40]. Although acute urinary retention is also a problem immediately after injection, the presence of retention is usually unrelated to the treatment outcome. Other adverse events such as haematuria, micturition pain and general weakness are generally transient [34,35]. The dose of BoNT is related to the occurrence of a large PVR or urinary retention needing CIC. Kuo [38] found that the rate of adverse events increased with increasing dose of BoNT for IDO; a dose of 200 U gave a 30% incidence of urinary retention, whereas none was found after injecting 100 U. Bladder base injection alone might also decrease the incidence of urinary retention [44]. Brubaker et al.[40], in their randomized clinical trial of onaBoNT-A on OAB in women also found a 34% incidence of a large PVR needing CIC.

One unmet need with bladder BoNT application is the prediction of responders and of who is at risk of developing retention. In a recent study, there was a large PVR needing CIC in 30% of patients treated with 200 U of onaBoNT-A [49]. In that study, a lower maximum flow rate, lower projected isovolumetric pressure and lower bladder contractility index were risk factors for incomplete emptying. However, another study of treatment with 200 U of onaBoNT-A was found to be safe in elderly patients, where the detrimental effect of retention on quality of life can be considerable [50]. Most experts report that difficult urination usually lasts a few weeks to 2–3 months, and will resolve, while patients maintain the clinical improvement for 6–9 months [26,29,35]. Moreover, a significant improvement in qualify of life has been reported with bladder BoNT injection for both NDO and IDO [51–53].

BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

There have only been few studies using BoNT in treatment of IC/BPS and non-infectious cystitis [54–60], listed in Table 1. The results suggest that BoNT-A treatment can modulate sensory transmission and reduce detrusor contractility. Although BoNT injection seems promising in treating symptoms of IC/BPS, long-term results need to be confirmed [54]. In a recent study, Kuo et al.[58] compared the therapeutic results of intravesical onaBoNT-A of 100 or 200 U plus hydrodistension and hydrodistension alone. Sixty-seven patients with IC/BPS in whom conventional treatments had failed were enrolled; 44 received a suburothelial injection with 200 U (15) or 100 U (29) of onaBoNT-A, followed by cystoscopic hydrodistension 2 weeks later (onaBoNT-A group). The control group (23 patients) received an identical hydrodistension procedure with no onaBoNT-A injection. The symptom score decreased in all three groups, but the reduction in pain scale, and increase in functional bladder capacity and cystometric bladder capacity were only in the onaBoNT-A groups at 3 months. Among 44 patients in the onaBoNT-A group, 31 (71%) had a successful result at 6 months, but only eight (35%) treated with hydrodistension had such a result (P < 0.001).

Table 1.  The therapeutic results of BoNT on cystitis
StudyN patientsClinical efficacyBoNT-A dose, U/sites
  1. VAS, visual analogue scale; (C)HD, (cystoscopic) hydrodistension.

[54]139/13 (69%) subjective improvement.100–200/20–30
Daytime frequency, nocturia and pain VAS decreased by 44%, 45%, and 79
[55]10Functional bladder capacity increased, 77 (27.1) vs 155 (26.3) mL, P < 0.001All 100 U (10 mL)/20, 5 received additional 100 U to trigone
Daily frequency reduced, 24.2 (10.3) vs 18 (7.7), P= 0.025
Pain score reduced, 3.2 (1.1) vs 2.4 (1.6), P= 0.003
[56]1412 reported subjective improvement at 1 and 3 months, VAS reduced frequency decreased and bladder capacity increased significantly200 U in 20 mL/20 including trigone and bladder base
2 reported dysuria and CIC was needed
[59]19At 3 months, 14 had symptomatic improvement (responders).19 with IC treated with 100 or 200 intravesical, followed by CHD 2 weeks later
NGF mRNA levels and immunostaining decreased significantly in responders and significantly decreased in 11 with a VAS pain scale reduction of ≥2
[57]15Overall 13 reported subjective improvement at the 1 and 3-month follow-up200 in 20 mL; submucosal in the bladder trigone and lateral walls
At 5-month follow-up beneficial effects persisted in 4 but increased daytime and night-time urinary frequency, and an increased VAS score vs baseline.
At 12 months after treatment pain recurred in all; 9 complained of dysuria
1 month after treatment. Dysuria persisted in 4 at 3-month follow-up and in 2 at 5-month follow-up
[60]8In 5/6 patients with radiation cystitis there was moderate to significant improvement; mean bladder capacity increased from 105 (25) to 250 (35) mL and urinary frequency decreased from 14 (2) to 11 (1) episodes/daySix with refractory radiation cystitis treated with 200 U bladder injections and 2 with cystitis after intravesical BCG treated with 100 U bladder injections
Both patients with BCG cystitis reported significant symptomatic improvement; the mean bladder capacity increased from 110 (23) to 230 (23) mL, urinary frequency decreased from 16 (1) to 12 (1) episodes/day, and using a 10-point VAS pain scoring system, the perceived pain score decreased from 8 to 2
[58]67Among 44 patients in BoNT-A group, 31 (71%) had a successful result at 6 months but only in 8 (35%) treated with HD (P < 0.001)44 had suburothelial 200 (15) or 100 U (29) followed by CHD 2 weeks later (BoNT-A group). Control group (23) received identical CHD with no BoNT-A injection
Symptom score decreased in all three groups, but pain scale reduction, functional bladder capacity and cystometric bladder capacity increased only in BoNT-A groups at 3 months

URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

The goals of urethral treatment are to lower the urethral resistance or detrusor leak-point pressure to promote bladder emptying, such that the upper urinary tracts are protected against a high bladder pressure. This treatment can be used in neurogenic bladder with DSD or in non-neurogenic voiding dysfunction, such as in urethral spasm and urethral non-relaxation. In general, there is a significant decrease in PVR and a significant reduction in urethral pressure [1,4]. The appearance of new stress urinary incontinence, and exacerbation of pre-existing incontinence due to sphincter denervation by BoNT are potential risks [61].

BoNT was at first used as a urethral sphincter injection to treat DSD in patients with SCI who did not desire surgery or were unable to use CIC [62]. Schurch et al.[63] reported that 21 of 24 patients with SCI benefited from onaBoNT-A injection. Although voiding becomes easier after urethral onaBoNT-A injection, urinary incontinence can be exacerbated in patients with NDO and DSD, which might prohibit continuing treatment.

In patients with dysfunctional voiding due to urethral sphincter overactivity, nonbacterial prostatitis and detrusor underactivity, BoNT has been shown to have a therapeutic effect in improving voiding efficiency and recovering detrusor contractility in several patients, with few reported adverse effects [64,65]. Phelan et al.[65] found that after BoNT injection, 67% of patients were able to void smoothly, with the PVR decreased by 71% and voiding pressure decreased by 38%. Eight patients with bladder-neck dyssynergia had 100 U of onaBoNT-A injected transurethrally into the bladder neck and proximal prostatic urethra laterally (10 U/mL × 10 sites). At 6 weeks, seven of the eight patients had a >50% reduction in the IPSS from baseline. Six of the eight patients had a >3 mL/s increase in peak urinary flow rate, with the overall mean peak urinary flow rates improving from 11.6 to 17.2 mL/s (P= 0.048) at 6 weeks. The voiding frequency decreased by 46% (13.6 vs 7.6, P= 0.036) and the mean (sd) IPSS quality of life score improved by 47%, from 4.9 (0.2) to 2.6 (0.6) (P= 0.048). No patients reported any adverse effects or ejaculatory dysfunction.

In a large series of 103 patients with voiding dysfunction, onaBoNT-A at 50 U (in 48) or 100 U (in 55) was injected, and 40 (39%) had an excellent result, 47 (46%) had an improvement and in 16 (15%) the treatment failed [66]. Among the patients with an improvement, those with detrusor underactivity due to a cauda equina lesion (62.5%) or idiopathic cause (61.5%) had the best result, whereas those with DSD (27.6%) ranked the last. The overall success rate was 84.5% (75–100%). Among the 45 patients with urinary retention, the indwelling catheters were removed or CIC was discontinued in 39 (87%) (Table 2). In an analysis of the patients with improvements, the voiding pressure, maximum urethral closure pressure and PVR all decreased significantly at 2 and 4 weeks after treatment. The mean voiding pressure decreased by 31.8%, maximum flow rate increased by 49.3%, PVR decreased by 60.8% and maximum urethral closure pressure decreased by 28.1%.

Table 2.  The therapeutic results of urethral BoNT injection [61]
ConditionN (%) of patients
TotalExcellentImprovedFailed
Neurogenic DSD 298 (28)15 (52)6 (21)
Dysfunctional voiding 206 (30)14 (70)0
Non-relaxing urethral sphincter 10874
Cauda equine lesion  8512
Peripheral neuropathy 14563
Idiopathic detrusor underactivity 13841
Totals10340 (39)47 (46)16 (16)

OnaBoNT-A at a dose of 50 U was effective in reducing urethral sphincter resistance among the patients with detrusor underactivity and difficult urination [61]. Of the four men and 15 women (age range 14–86 years) with voiding dysfunction, 18 (90%) were treated satisfactorily. The median (sd) voiding pressure decreased from 56.5 (41.2) to 39.0 (32.1) cmH2O and the PVR from 300 (189.1) to 50 (153.6) mL at 2 weeks after treatment and remained stationary for 3 months. In seven patients the indwelling catheters were removed, and in four who used CIC the frequency decreased or it was discontinued. The other seven patients with difficult urination had a significant improvement in the obstructive symptom score, from 18 (3.3) to 7 (4.5) (P < 0.001).

Patients after radical hysterectomy for cervical cancer can have difficult urination due to detrusor underactivity and a non-relaxing urethral sphincter. Urethral injection with BoNT can be used effectively to treat lower urinary tract dysfunction in these patients [67]. Thirty patients with difficult urination after radical hysterectomy due to cervical cancer were enrolled to receive a urethral injection of 100 U of onaBoNT-A (20) or medical treatment as controls (10). After urethral BoNT injection, eight patients had an excellent result (40%) and eight had an improvement (40%) in the study group. Both voiding pressure and PVR significantly improved after treatment. The maximum effect appeared at ≈1 week after treatment. The duration of therapeutic effect was 3–9 months. Mild stress urinary incontinence and nocturnal enuresis were reported in seven patients (35%).

TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

Each vial of 100 U onaBoNT-A is usually reconstituted to 4 mL with normal saline, making the concentration equivalent to 25 U/mL. In all, 50 or 100 U of BoNT-A is injected into the urethral sphincter at the 3, 6, 9 and 12-o’clock positions in approximately equal aliquots, using a cystoscopic injection instrument in men [56]. Cystoscopy is advised in women and the axis of the urethra is determined for proper injection positions, and BoNT is injected into the urethral sphincter along the urethral lumen at the 3, 6, 9 and 12 o’clock positions of the sides of urethral meatus, using a 23-G 1-mL syringe (Fig. 2A). In men, BoNT is injected at the circumferential sites of the urethral sphincter (Fig. 2B). If 50 U of onaBoNT-A is injected, 0.5 mL is used for each injection; when 100 U is injected, 1 mL is used for each injection [67].

image

Figure 2. Urethral sphincter BoNT injection. (A) In women, the urethra is injected along the urethral lumen at the 3, 6, 9 and 12 o’clock positions of the sides of urethral meatus. (B) In men, the injections are delivered at the circumferential sites of the urethral sphincter. (C) Urethral injections for men with urethral dysfunction, each 1 mL of BoNT solution is injected to two sites over the trigone, bladder neck, proximal and distal prostatic urethra and the external urethral sphincter.

Download figure to PowerPoint

For patients receiving urethral BoNT injections, 100 U is dissolved in 10 mL and each 1 mL of BoNT solution is injected into two sites over the trigone, bladder neck, proximal prostatic urethra, distal prostatic urethra and the external urethral sphincter [68] (Fig. 2C). The injections should be superficial, without injecting solution into the prostate gland. While injecting the urethral sphincter it is essential to inject BoNT directly into it; using too much solution might force BoNT solution to leak outside the urethral sphincter and result in an inadequate treatment dose. The injection needle should not be inserted too deeply (<1 cm) to avoid injecting BoNT outside the sphincter muscle or into the bladder lumen. The dose of onBoNT-A can be 50–100 U for patients with detrusor underactivity who wish to void by abdominal pressure after treatment, or 100 U for patients with DSD, dysfunctional voiding or poor relaxation of the urethral sphincter [63–66]. Medications for reducing urethral resistance can be discontinued after the BoNT injections [67,69].

PROSTATE BoNT APPLICATION

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

Physical denervation of the prostate by sectioning the hypogastric nerve in a rat model induces prostatic atrophy [70]. Similarly, Doggweiler et al.[71], using chemical denervation by injecting BoNT into the rat prostate, reported a generalized atrophy and apoptosis of glandular elements. Cholinergic innervation of the prostate gland has an important role in regulating the functions of the prostate epithelium, with effects on growth and secretion, while the noradrenergic innervation has been implicated in the contraction of smooth muscle and aetiology of outlet obstruction accompanying BPH [72]. In rats as well as in dogs, BoNT induces prostatic gland atrophy, and in some cases apoptosis [71,73]. Lin et al.[74] reported that injection with 200 U of onaBoNT-A into the canine prostate significantly reduced the prostate urethral pressure response to i.v. noradrenaline and to electrostimulation [74]. They concluded that BoNT reduces the contractile function of the prostate and might attenuate the dynamic component of BPH. It appears that intraprostatic BoNT injection is effective in relieving the symptoms of BPH to different degrees. Different doses, dilution volume, and prostate component might lead to different results. The effect is reported to last ≥6 months [6,72,75–81] (Table 3).

Table 3.  The therapeutic results of BoNT for prostate treatment
StudyChange and % changeFollow-up, months
PSA, ng/mLPVR, mLPV, mLQmax, mL/sQoLIPSSPI
  1. * P < 0.05, P < 0.01; P < 0.001; NA, not available; PV, prostate volume; Qmax, maximum urinary flow rate; QoL, IPSS quality of life score; PI, patients included.

[6]3.7 to 1.8126.3 to 2152.6 to 16.88.1 to 15.423.2 to 813 (15)2
51%83%68% 65%  
[72]NA177.6 to 24.561.6 to 507.5 to 12.93.9 to 2.1From 19 to 5 8 (8)1
 86.2%18.8%*72%*61.5%*73%*  
[76]0.8 to 0.7267.7 to 25.119.6 to 177.3 to 11.83.8 to 2.118.8 to 8.916 (16)1
NA63%, NA13.3%39.8%44.7%52.6%  
[77]
100 UNA64.2 to 35.721.1 to 187.9 to 123.9 to 2.118.7 to 9.831 ( 41)1
 44%15%62%46%48%  
200 UNA161.7 to 45.254.3 to 46.37 to 10.34.1 to 219.3 to 9.510 (41)1
 72%*15%47%51%51%  
[75]NA243.5 to 36.865.5 to 49.67.6 to 11.64.5 to 2.1NA10 (10)6
 *   
[78]2.6 to 2.4122.7 to 84.747.2 to 429.6 to 11.1NA24.3 to 16.939 (52)3
NA34%*13.1%*15.5%*30.3%*  
[79]6 to 50 to 9270 to 470 to 10.3NANA10 (10)3
*     
[80]25% decrease55 to 8282 to 49 (6 m)11.3 to 11.3NA10 to 12 11 (11)18
  73 (18 m)     
[81]6.2 to 4.8*92.1 to 80.354.1 to 47.28.6 to 13.1NA24.1 to 12.641 (77)1
6.2 to 3.092.1 to 40.654.1 to 30.98.6 to 16.5NA24.1 to 8.755 (77)2
3.0 to 3.140.6 to 27.1*30.9 to 26.916.5 to 14.5*NA8.7 to 11.1*55 + 22 (77)30

TECHNIQUE OF PROSTATE BoNT INJECTION

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

The prostate can be injected with BoNT transperineally, transrectally or transurethrally, with the preference often dictated by regional practice habits. Transperineal injection minimizes the risk of infection but TRUS-guided transrectal prostatic injection is the procedure with which urologists are most familiar in Europe and North America. The preparation and positioning of the patient is identical to that used for transrectal or transperineal ultrasonography-guided prostate biopsy (Fig. 3A). Some urologists might prefer transurethral prostate injection using a familiar cystoscope and injecting needle to approach the enlarged prostate (Fig. 3B).

image

Figure 3. Technique of prostatic BoNT injection. (A) Patients are placed in the lithotomy position, a TRUS probe inserted through the anus and an injection needle inserted transperineally. (B) Transurethral injection of the prostate (C) Under TRUS guidance, the injection needle is inserted into one lobe of the prostate; the needle can be easily identified and inserted into the prostate. (D) After injection of the BoNT solution into one lobe, the BoNT solution diffuses to the prostate lobe homogeneously.

Download figure to PowerPoint

During treatment, onaBoNT-A 200 U is reconstituted by normal saline to 4 mL or ≈10% of the total prostate volume, and is injected at two sites. Lidocaine local anaesthesia is optional, as a clinician preference. We used a 21-G, 15 or 20 cm long needle under TRUS guidance, with transverse and sagittal views to ensure proper placement of the needle as a bright spot in the centre of each lateral lobe, where 2 mL of BoNT was injected into each side (Fig. 3C). Diffusion of hyperechoic BoNT over the lateral lobe of the prostate can be easily seen with TRUS monitoring (Fig. 3D). Antibiotic cover and preparation are similar to what we use for TRUS-guided prostate biopsy (Table 3).

POTENTIAL FOR LIQUID INSTILLATION OF BoNT

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

The development of instillation as a method for administering BoNT in patients might drastically decrease the side-effects and treatment cost. There is a recent report of using of dimethyl sulphoxide (DMSO) for liquid BoNT bladder instillation [82]. DMSO does not maintain the natural state of the BoNT protein, and must be formulated immediately before instillation. Dissolving BoNT in DMSO might not be advisable, because of concerns about BoNT uptake into the systemic circulation of the patient, and potentially absorption of DMSO by the administering clinician. Moreover, biochemical studies showed that the metalloproteolytic activity of the BoNT is strongly enhanced by the presence of lipid membranes [83].

Recent studies reaffirmed the potential of liposomes as a promising vehicle for delivery of neurotoxins in the bladder [84]. Liposomes are biocompatible delivery agents in the bladder. The transport of BoNT into urothelium from liposomes (Lipella Pharmaceuticals, Pittsburgh, PA, USA) was confirmed by detection of its unique effect on neurotransmitters and proteolysis of SNAP-25 by immunohistochemistry. The protection to BoNT entrapped inside liposomes from degradation in urine, without compromising efficacy, was confirmed by the attenuation of acetic acid-induced bladder irritation in rats. Similar results were obtained in preclinical studies with liposomes encapsulating capsaicin. These results support liposomes as an efficient vehicle for delivering BoNT without injection, and support clinical trials with liposomal formulations of BoNT to assess efficacy and risk of retention.

The development of a simpler and effective method for the BoNT delivery into the bladder without the need for injection, and with a lower risk of urinary retention, is an exciting area of research.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES

BoNT is effective across a wide variety of LUTS that involve muscular hypercontractility, hypersensitivity, and glandular hypertrophy. Advances have been made in our understanding of how BoNT works, and its clinical application and results. As the use of BoNT in the urethra, bladder or prostate is currently ‘off-label’ in many countries, caution should be applied until larger randomized clinical studies are completed.

CONSIDERATIONS FOR THE SAFE USE OF BoNT

Healthcare professionals should be aware that a boxed warning has been added to the prescribing information of BoNT in the USA, to highlight that BoNT can spread from the area of injection to produce symptoms consistent with botulism.

Symptoms such as unexpected loss of strength or muscle weakness, hoarseness or trouble talking (dysphonia), trouble saying words clearly (dysarthria), loss of bladder control, trouble breathing, trouble swallowing, double vision, blurred vision and drooling eyelids may occur.

Understand that swallowing and breathing difficulties can be life-threatening and there have been reports of deaths related to the effect of spread of BoNT.

Be aware that children treated for spasticity are at greatest risk of these symptoms, but symptoms can also occur in adults treated for spasticity and other conditions.

Realise that cases of toxin spread have occurred at BoNT doses comparable to those used to treat cervical dystonia and at lower doses.

Understand that BoNT products are not interchangeable and that the established drug names of the BoNT products have been changed to emphasize the differing dose to potency rations of these products. The doses expressed in units are not comparable from one BoNT product to the next. Units of one product cannot be converted into units of another product.

Available BoNT (only BoNT-A and B are in clinical use). The potency of each toxin is expressed in units of activity. Although there are similarities among the commercial preparations of BoNT, they have different doses, efficacy and safety profiles and should not be considered generic equivalents comparable by single dose ratios:

  • 1
    OnaBoNT-A (Botox; Allergan, Inc., Irvine, CA)
  • 2
    AboBoNT-A (Dysport; Ipsen Ltd, Berkshire, UK)
  • 3
    RimaBoNT-B (Myobloc; Elan Pharmaceuticals, Inc., Princeton, NJ).

REFERENCES

  1. Top of page
  2. Abstract
  3. A BRIEF HISTORY OF BOTULINUM NEUROTOXIN (BoNT)
  4. HOW BoNT WORKS
  5. HOW DOES BoNT ACHIEVE MONTHS OF CLINICAL EFFICACY?
  6. RATIONALE FOR USING BoNT IN THE LOWER URINARY TRACT
  7. CLINICAL USE IN THE BLADDER
  8. A RANDOMIZED CONTROLLED TRIAL OF BoNT FOR OAB
  9. INJECTION TECHNIQUES
  10. ADVERSE EVENTS OF BoNT
  11. BoNT FOR IC/BPS AND NON-INFECTIOUS CYSTITIS
  12. URETHRAL SPHINCTER AND PELVIC FLOOR INJECTION
  13. TECHNIQUES OF URETHRAL SPHINCTER BoNT INJECTION
  14. PROSTATE BoNT APPLICATION
  15. TECHNIQUE OF PROSTATE BoNT INJECTION
  16. POTENTIAL FOR LIQUID INSTILLATION OF BoNT
  17. CONCLUSIONS
  18. CONFLICT OF INTEREST
  19. REFERENCES
  • 1
    Smith CP, Chancellor MB. Emerging role of botulinum toxin in the treatment of voiding dysfunction. J Urol 2004; 171: 212837
  • 2
    Aoki KR, Guyer B. Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions. Eur J Neurol 2001; 8 (Suppl. 5): 219
  • 3
    Aoki KR. A comparison of the safety margins of Botulinum neurotoxin serotypes A, B, and F in mice. Toxicon 2001; 39: 181520
  • 4
    Dykstra DD, Sidi AA, Scott AB, Pagel JM, Goldish GD. Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients. J Urol 1988; 139: 91922
  • 5
    Schurch B, Stohrer M, Kramer G, Schmid DM, Gaul G, Hauri D. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: a new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164: 6927
  • 6
    Maria G, Brisinda G, Civello IM, Bentivoglio AR, Sganga G, Albanese A. Relief by botulinum toxin of voiding dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-controlled study. Urology 2003; 62: 25964
  • 7
    Kozaki S, Miki A, Kamata Y, Ogasawara J, Sakaguchi G. Immunological characterization of papain-induced fragments of Clostridium botulinum type A neurotoxin and interaction of the fragments with brain synaptosomes. Infect Immun 1989; 57: 26349
  • 8
    Dong M, Yeh F, Tepp WH et al. SV2 is the protein receptor for botulinum neurotoxin A. Science 2006; 312: 5926
  • 9
    Modugno N, Priori A, Berardelli A, Vacca L, Mercuri B, Manfredi M. Botulinum toxin restores presynaptic inhibition of group Ia afferents in patients with essential tremor. Muscle Nerve 1998; 21: 17015
  • 10
    Smith CP, Boone TB, De Groat WC, Chancellor MB, Somogyi GT. Effect of stimulation intensity and botulinum toxin isoform on rat bladder strip contractions. Brain Res Bull 2003; 61: 16571
  • 11
    Thesleff S, Molgo J, Tågerud S. Trophic interrelations at the neuromuscular junction as revealed by the use of botulinal neurotoxins. J Physiol (Paris) 1990; 84: 16773
  • 12
    De Paiva A, Meunier FA, Molgó J, Aoki KR, Dolly JO. Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals. Proc Natl Acad Sci USA 1999; 96: 32005
  • 13
    Haferkamp A, Schurch B, Reitz A et al. Lack of ultrastructural detrusor changes following endoscopic injection of botulinum toxin type a in overactive neurogenic bladder. Eur Urol 2004; 46: 78491
  • 14
    Compérat E, Reitz A, Delcourt A, Capron F, Denys P, Chartier-Kastler E. Histologic features in the urinary bladder wall affected from neurogenic overactivity – a comparison of inflammation, oedema and fibrosis with and without injection of botulinum toxin type A. Eur Urol 2006; 50: 105864
  • 15
    Apostolidis A, Jacques TS, Freeman A et al. Histological changes in the urothelium and suburothelium of human overactive bladder following intradetrusor injections of botulinum neurotoxin type A for the treatment of neurogenic or idiopathic detrusor overactivity. Eur Urol 2008; 53: 124553
  • 16
    Aoki KR. Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A. Neurotoxicology 2005; 26: 78593
  • 17
    Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin type A reduces formalin-induced pain. Pain 2004; 107: 12533
  • 18
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Chancellor MB. Intravesical botulinum toxin A administration produces analgesia against acetic acid induced bladder pain responses in rats. J Urol 2004; 172: 152932
  • 19
    Khera M, Somogyi GT, Kiss S, Boone TB, Smith CP. Botulinum toxin A inhibits ATP release from bladder urothelium after chronic spinal cord injury. Neurochem Int 2004; 45: 98793
  • 20
    Smith CP, Gangitano DA, Munoz A et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Intl 2008; 52: 106875
  • 21
    Apostolicism A, Poppet R, Yangon Y et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of Botulinum toxin for human detrusor overactivity. J Urol 2005; 174: 97782
  • 22
    Giannantoni A, Di Stasi SM, Nardicchi V et al. Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol 2006; 175: 23414
  • 23
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Wu M, Chancellor MB. Intraprostatic capsaicin injection as a novel model for non-bacteria prostatitis. Eur Urol 2007; 51: 111927
  • 24
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Wu M, Chancellor MB. Intraprostatic botulinum toxin A injection inhibits COX-2 expression and suppresses prostatic pain on capsaicin induced prostatitis model in rat. J Urol 2008; 180: 7428
  • 25
    Chuang YC, Yoshimura N, Huang CC, Chiang PH, Wu M, Chancellor MB. Intravesical botulinum toxin A administration inhibits COX-2 and EP4 expression and suppresses bladder hyperactivity in cyclophosphamide induced cystitis in rats. Eur Urol 2009; 56: 15966
  • 26
    Sahai A, Khan MS, Dasgupta P. Efficacy of botulinum toxin-A for treating idiopathic detrusor overactivity: results from a single center, randomized, double-blind, placebo controlled trial. J Urol 2007; 177: 22316
  • 27
    Schurch B, De Seze M, Denys P et al. Botox Detrusor Hyperreflexia Study Team. Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled6-month study. J Urol 2005; 174: 196200
  • 28
    Giannantoni A, Mearini E, Del Zingaro M. Six-year follow-up of BoNT-A intradetrusorial injections in patients with refractory neurogenic detrusor overactivity: clinical and urodynamic results. Eur Urol 2009; 55: 70511
  • 29
    Chancellor MB. Ten years single surgeon experience with botulinum toxin in the urinary tract; clinical observations and research discovery. Int Urol Nephrol 2009; Epub ahead of print, DOI 101.1007/s11255-009-9600-7
  • 30
    Kessler TM, Danuser H, Schumacher M, Studer VE, Burkhard FC. Botulinum A toxin injections into the detrusor: an effective treatment in idiopathic and neurogenic detrusor overactivity? Neurourol Urodyn 2005; 24: 2316
  • 31
    Rajkumar GN, Small DR, Mustafa AW, Conn G. A prospective study to evaluate the safety, tolerability, efficacy and durability of response of intravesical injection of botulinum toxin type A into detrusor muscle in patients with refractory idiopathic detrusor overactivity. BJU Int 2005; 96: 84852
  • 32
    Popat R, Apostolidis A, Kalsi V, Gonzales G, Fowler CJ, Dasgupta P. A comparison between the response of patients with idiopathic detrusor overactivity and neurogenic detrusor overactivity to the first intradetrusor injection of botulinum-A toxin. J Urol 2005; 174: 9849
  • 33
    Schulte-Baukloh H, Weiss C, Stolze T, Sturzebecher B, Knispel HH. Botulinum-A toxin for treatment of overactive bladder without detrusor overactivity: urodynamic outcome and patient satisfaction. Urology 2005; 66: 827
  • 34
    Kuo HC. Urodynamic evidence of effectiveness of botulinum A toxin injection in treatment of detrusor overactivity refractory to anticholinergic agents. Urology 2004; 63: 86872
  • 35
    Kuo HC. Clinical effects of suburothelial injection of botulinum A toxin in patients with non-neurogenic detrusor overactivity refractory to anticholinergics. Urology 2005; 66: 948
  • 36
    Werner M, Schmid DM, Schussler B. Efficacy of botulinum-A toxin in the treatment of detrusor overactivity incontinence: a prospective nonrandomized study. Am J Obstet Gynecol 2005; 192: 173540
  • 37
    Schmid DM, Sauermann P, Werner M et al. Experience with 100 cases treated with botulinum-A toxin injections in the detrusor muscle for idiopathic overactive bladder syndrome refractory to anticholinergics. J Urol 2006; 176: 17785
  • 38
    Kuo HC. Will suburothelial injection of a small dose of botulinum A toxin have similar therapeutic effects and less adverse events for refractory detrusor overactivity? Urology 2006; 68: 9937
  • 39
    Ghei M, Maraj BH, Miller R et al. Effects of botulinum toxin B on refractory detrusor overactivity: a randomized, double-blind, placebo controlled, crossover trial. J Urol 2005; 174: 18737
  • 40
    Brubaker L, Richter HE, Visco A et al. Refractory idiopathic urge urinary incontinence and botulinum A injection. J Urol 2008; 180: 21722
  • 41
    Dmochowski R, Chapple C, Nitti V et al. Efficacy and safety of botulinum toxin A (onabotulinumtoxinA) in idiopathic overactive bladder: a double-blind, placebo-controlled, randomized, dose-ranging trial (presented at the 2009 Western Section of the AUA meeting). J Urol 2010 (in press)
  • 42
    Mehnert U, Boy S, Schmid M et al. A morphological evaluation of botulinum neurotoxin A injections into the detrusor muscle using magnetic resonance imaging. World J Urol 2009; 27: 397403
  • 43
    Kuo HC, Chen YC, Chen CY, Chancellor MB. Trans-abdominal ultrasound measurement of detrusor wall thickness in patients with overactive bladder. Tzu Chi Med J 2009; 21: 12935
  • 44
    Kuo HC. Comparison of effectiveness of detrusor, suburothelial and bladder base injections of botulinum toxin A for idiopathic detrusor overactivity. J Urol 2007; 178: 135963
  • 45
    Zermann DH, Ishigooka M, Schubert J et al. Trigonum and bladder base injection of botulinum toxin A (BTX) in patients with severe urgency–frequency-syndrome refractory to conservative medical treatment and electrical stimulation. Neurourol Urodyn 2001; 20: 4123
  • 46
    Karsenty G, Elzayat E, Delapparent T, St-Denis B, Liemileux MC, Corcus J. Botulinum toxin type a injections into the trigone to treat idiopathic overactive bladder do not induce vesicoureteral reflux. J Urol 2007; 177: 10114
  • 47
    Mascarenhas F, Cocuzza M, Gomes CM, Leão N. Trigonal injection of botulinum toxin-A does not cause vesicoureteral reflux in neurogenic patients. Neurourol Urodyn 2008; 27: 3114
  • 48
    Kalsi V, Apostolidis A, Gonzales G, Elneil S, Dasgupta P, Fowler CJ. Early effect on the overactive bladder symptoms following botulinum neurotoxin type A injections for detrusor overactivity. Eur Urol 2008; 54: 1817
  • 49
    Sahai A, Sangster P, Kalsi V, Khan MS, Fowler CJ, Dasgupta P. Assessment of urodynamic and detrusor contractility variables in patients with overactive bladder syndrome treated with botulinum toxin-A: is incomplete bladder emptying predictable. BJU Int 2009; 103: 6304
  • 50
    White WM, Pickens RB, Doggweiller R, Klein FA. Short-term efficacy of botulinum toxin a for refractory overactive bladder in the elderly population. J Urol 2008; 180: 25226
  • 51
    Schurch B, Denys P, Kozma CM et al. Botulinum toxin A improves the quality of life of patients with neurogenic urinary incontinence. Eur Urol 2007; 52: 8508
  • 52
    Schulte-Baukloh H, Schobert J, Stolze T et al. Efficacy of botulinum-A bladder injections for the treatment of neurogenic detrusor overactivity in multiple sclerosis patients: an objective and subjective analysis. Neurourol Urodyn 2006; 25: 1105
  • 53
    Reitz A, Stohrer M, Kramer G et al. European experience of 200 cases treated with botulinum-A toxin injections into the detrusor muscle for urinary incontinence due to neurogenic detrusor overactivity. Eur Urol 2004; 45: 5105
  • 54
    Smith CP, Radziszewski P, Borkowski A et al. Botulinum toxin A has antinociceptive effects in treating interstitial cystitis. Urology 2004; 64: 8715
  • 55
    Kuo HC. Preliminary results of suburothelial injection of botulinum A toxin in the treatment of chronic interstitial cystitis. Urol Int 2005; 75: 1704
  • 56
    Giannantoni A, Costantini E, Di Stasi SM, Tascini MC, Bini V, Porena M. Botulinum A toxin intravesical injections in the treatment of painful bladder syndrome: a pilot study. Eur Urol 2006; 49: 7049
  • 57
    Giannantoni A, Porena M, Costantini E et al. Botulinum A toxin intravesical injection in patients with painful bladder syndrome: 1-year followup. J Urol 2008; 179: 10314
  • 58
    Kuo HC, Chancellor MB. Comparison of intravesical botulinum toxin type A injections plus hydrodistention with hydrodistention alone for the treatment of refractory interstitial cystitis/painful bladder syndrome. BJU Int 2009; 104: 65761
  • 59
    Liu HT, Kuo HC. Intravesical botulinum toxin A injections plus hydrodistension can reduce nerve growth factor production and control bladder pain in interstitial cystitis. Urology 2007; 70: 4638
  • 60
    Chuang CC, Kim DK, Chiang PH, Chancellor MB. Bladder botulinum toxin A injection can benefit patients with radiation and chemical cystitis. BJU Int 2008; 012: 7046
  • 61
    Kuo HC. Effect of botulinum A toxin in the treatment of voiding dysfunction due to detrusor underactivity. Urology 2003; 61: 5504
  • 62
    Dykstra DD, Sidi AA. Treatment of detrusor-sphincter dyssynergia with botulinum A toxin: a double-blind study. Arch Phys Med Rehabil 1990; 71: 246
  • 63
    Schurch B, Hauri D, Rodic B, Curt A, Meyer M, Rossier AB. Botulinum A toxin as a treatment of detrusor sphincter dyssynergia: a prospective study in 24 spinal cord injury patients. J Urol 1996; 155: 10239
  • 64
    Maria G, Destito A, Lacquaniti S et al. Relief by botulinum toxin of voiding dysfunction due to prostatitis. Lancet 1998; 352: 625
  • 65
    Phelan MW, Franks M, Somogyi GT et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol 2001; 165: 110710
  • 66
    Lim SK, Quek PL. Intraprostatic and bladder-neck injection of botulinum A toxin in treatment of males with bladder-neck dyssynergia: a pilot study. Eur Urol 2008; 53: 6205
  • 67
    Kuo HC. Effectiveness of treatment of voiding dysfunction after radical hysterectomy by botulinum A toxin urethral injection. Urol Int 2005; 75: 24751
  • 68
    Chen JL, Chen CY, Kuo HC. Botulinum toxin A injection to the bladder neck and urethra for medically refractory lower urinary tract symptoms in men without prostatic obstruction. J Formos Med Assoc 2009; 108: 9506
  • 69
    Kuo HC. Recovery of detrusor function after urethral botulinum A toxin injection in patients with idiopathic low detrusor contractility and voiding dysfunction. Urology 2007; 69: 5761
  • 70
    Pennefather JN, Lau WAK, Mitchelson F, Ventura S. The autonomic and sensory innervation of the smooth muscle of the prostate gland: a review of pharmacological and histological studies. J Auton Pharmacol 2000; 20: 193206
  • 71
    Doggweiler R, Zermann DH, Ishigooka M, Schmidt RA. Botox induced prostatic involution. Prostate 1998; 37: 44
  • 72
    Chuang YC, Chancellor MB. The application of Botulinum toxin in the prostate. J Urol 2006; 176: 237686
  • 73
    Chuang YC, Huang CC, Kang HY et al. Novel action of Botulinum toxin on the stromal and epithelial components of prostate gland. J Urol 2006; 173: 115863
  • 74
    Lin ATL, Yang AH, Chen KK. Effect of Botulinum toxin A on the contractile function of dog prostate. Eur Urol 2007; 52: 5829
  • 75
    Kuo HC. Prostate botulinum toxin A injection- an alternative treatment for benign prostatic obstruction in poor surgical candidates. Urology 2005; 65: 6704
  • 76
    Chuang YC, Chiang PH, Huang CC et al. Botulinum toxin type A improves benign prostatic hyperplasia symptoms in patients with small prostates. Urology 2005; 66: 7759
  • 77
    Chuang YC, Chiang PH, Yoshimura N et al. Sustained beneficial effects of intraprostatic botulinum toxin type A injection on lower urinary tract symptoms and quality of life in men with benign prostatic hyperplasia. BJU Int 2006; 98: 10337
  • 78
    Park DS, Cho TW, Lee YK et al. Evaluation of short term clinical effects and presumptive mechanism of botulinum toxin type A as a treatment modality of benign prostatic hyperplasia. Yonsei Med J 2006; 31: 70614
  • 79
    Silva J, Silva C, Saraiva L et al. Intraprostatic botulinum toxin type A injection in patients unfit for surgery presenting with refractory urinary retention and benign prostatic enlargement: effect on prostate Volume and micturition resumption. Eur Urol 2008; 53: 1539
  • 80
    Silva J, Pinto R, Carvalho T et al. Intraprostatic botulinum toxin type A injection in patients with benign prostatic enlargement: duration of the effect of a single treatment. BMC Urol 2009; 9: 9
  • 81
    Brisinda G, Cadeddu F, Vanella S, Mazzeo P, Marniga G, Maria G. Relief by botulinum toxin of lower urinary tract symptoms owing to benign prostatic hyperplasia: early and long-term results. Urology 2009; 73: 904
  • 82
    Petrou SP, Parker AS, Crook JE et al. Botulinum a toxin/dimethyl sulfoxide bladder instillations for women with refractory idiopathic detrusor overactivity: a phase1/2 study. Mayo Clin Proc 2009; 84: 7026
  • 83
    Caccin P, Rossetto O, Rigoni M, Johnson E, Schiavo G, Montecucco C. VAMP/synaptobrevin cleavage by tetanus and botulinum neurotoxins is strongly enhanced by acidic liposomes. FEBS Lett 2003; 542: 1326
  • 84
    Chuang YC, Tyagi P, Huang CC et al. Urodynamic and immunohistochemical evaluation of intravesical botulinum toxin A delivery using liposomes. J Urol 2009; 182: 78692