**8. Perspectives of Botulinum Toxin A on Sensory Bladder Disorders**

Intravesical BoNT-A injection for OAB and IC have been demonstrated to be effective and well tolerated. However, large PVR and difficulty with urination remain problems to be solved [80]. Patients with OAB can benefit from BoNT-A for urgency and urgency incontinence relief, and patients with IC can have bladder pain relief after BoNT-A injection. However, for patients with bladder oversensitivity who do not have urgency or bladder pain, the adverse events that occurr after BoNT-A might not be acceptable [116].

Liposome instillation into the inflammatory bladder models have been shown effective to treat bladder hyperactivity in rat models [117]. As BoNT-A has a large molecular weight of 150 kDa, this neurotoxin cannot be delivered across the bladder urothelial cell membrane without an injection. Liposome encapsulated BoNT-A has also been demonstrated effective in improving the acetic acid-induced bladder hyperactivity in rat models [118]. The rats that received liposome encapsulated BoNT-A (Lipotoxin) showed significant decrease of response to acetic acid pretreatment without compromising the voiding function. Lipotoxin treatment also showed cleavage of SNAP-25, inhibition of CGRP from afferent nerves and blockage of hyperactivity induced by acetic acid. This evidence supports the idea that liposome can effectively carry BoNT-A across the urothelial barrier and has effects on bladder inflammation.

In a proof-of-concept clinical trial, Kuo et al. found that the BoNT-A binding protein SV2 could be demonstrated in the apical cells, urothelial cells and suburothelial tissues of the normal and OAB patients by immunohistochemistric or western blotting studies [119]. The changes of three-day urinary frequency (−6.50, IQR −18.3 to −0.25) and urgency (−12.0, IQR −20.3 to −2.75) significantly improved in the Lipotoxin group but not in the control group at one month post intravesical instillation of Lipotoxin containing 80 mg of liposome and 200 U of BoNT-A or normal saline [119]. A multicentric double-blind randomized trial using the same regimens also demonstrated that a single intravesical instillation of Lipotoxin could significantly decrease OAB symptoms and three-day frequency episodes (−4.64 for Lipotoxin and −0.19 for placebo, *p* = 0.0252) without adverse events of dysuria, large PVR or urinary tract infection [120].

Another recent study using Lipotoxin (containing 80 mg of liposome and 200 U of BoNT-A) for treatment of IC refractory to conventional medication revealed that a single Lipotoxin instillation was associated with a significant decrease in O'Leary-Sant symptom score (mean 7.38 ± 8.75), ICSI (4.00 ± 4.28), ICPI (3.35 ± 5.11) and VAS (1.64 ± 2.52); and an increase in the GRA score (1.35 ± 1.28). However, patients allocated to receive normal saline or BoNT-A in saline also had similar results [121]. Although the results of this study were negative, the effect of Lipotoxin on urinary frequency is similar to the results from Lipotoxin on OAB patients [120]. As patients with OAB or IC have symptom improvement, no difficulty with urination or large PVR after Lipotoxin intravesical instillation, this suggests that the penetration depth of BoNT-A carried by liposome is not as deep as that of a detrusor injection. The effect of BoNT-A in liposome might be limited to the urothelium. It seems rational to treat patients with bladder oversensitivity by liposome encapsulated BoNT-A rather than detrusor injection. However, the therapeutic duration of Lipotoxin instillation is short and the study was carried out in a small number of patients, indicating that the amount of BoNT-A protein diffused into the bladder urothelium was small. A large, randomized control trial is needed to clarify the effect of Lipotoxin on bladder oversensitivity.

Recently, low energy shock wave (LESW) has been enthusiastically applied in treatment of lower urinary tract disorders in animal models for bladder inflammation and overactivity [122,123]. LESWs suppressed cyclophosphamide-induced bladder pain, inflammation, and overactivity involved with the activation of IL6, NGF, and COX2 expression, indicating that it is a potential candidate for relieving bladder inflammatory conditions and overactivity [123]. LESWs also increased urothelial permeability, facilitated intravesical BoNT-A delivery and blocked acetic acid-induced hyperactive bladder [124]. In a preliminary clinical study including 15 patients with refractory OAB, Nageib et al. used intravesical instillation of 100 U of BoNT-A followed by LESWs (3000 shocks over 10 min) of exposure to the supra-pubic area. They found significant improvements in all OABSS domains and a total score at one and two months after treatment without an increase of PVR. [125] In the future, BoNT-A might be delivered via LESW to treat bladder oversensitivity without a need of intravesical injection.
