Overactive Bladder Clinical Trial
Official title:
Delivery of Intravesical Botulinum Toxin A Using Low Energy Shock Waves in Treatment of Overactive Bladder: A Feasibility Study
We hypothesize that LESWs might temporarily increase urothelial permeability and facilitate delivery of intravesical botulinum toxin without the need for injection.
High energy extracorporeal shock wave thrapy has been used to disintegrate urolithiasis for
30 years (Chaussy et al., 1982). Low energy shock wave LESWs are used clinically to improve
tissue regeneration at tendon- bone junctions (Wang et al., 2003) , ischemic cardiovascular
disorders (Dimeglio et al., 2012) and erectile dysfunctions (Vardi et al., 2012).
Furthermore, shock waves have been shown to temporarily increase tissue permeability (Lauer
et al., 1997, Kodama et al., 2002) and increase mediated molecular and drug delivery into
cells without consequent cytotoxicity. Kodama et al., 2002 suggested that shock waves could
cause shear force generated by the movement of liquid relative to cells to temporarily affect
the permeability of the plasma memberance. Shock waves can deliver molecules to 2,000,000
molecular weight into the cystoplasm of cells without toxicity (Lauer et al., 1997).
Instillation of drugs in the bladder provides the opportunity to locally increase drug
concentration with a low risk of systemic side effects (Kuo et al., 2010, Hsu et al., 2013).
Intravesical pharmacotherapy has been used to treat refractory overactive bladder and
interstitial cystitis/ painful bladder syndrome (smith et al., 2004; Grannantoni et al.,
2008; Boy et al., 2006). However, drug delivery to bladder tissues by intravesical route is
constrained by urothelial impermeability. The watertight barrier is generally located at the
umbrella cells, which are the superficial layers of bladder epithelium augmented by
glycosaminoglycans and uroplakins (Hsu et al., 2013; Birder et al., 2005).
Transient permeabilization of cell membranes accomplished by shock waves can deliver
macromolecular drugs in the bladder without toxicity (Lower et al., 1997; Kodama et al.,
2002).
Chuang et al., (2016) demonstrated that contrast enhanced MRI can detect increased rat
bladder permeability after LESWs. Recently, Towner et al (2015) reported increased urothelial
permeability and contrast leakage on bladder MRI after intravesical promtamine sulfate
instillation.
Chen et al., (2014) found that LESWs treatment 3 and 24 hours after cyclophosphamide
administration could attenuate cyclophosphamide induced acute cystitis in rats by decreasing
inflammation and oxidative stress.
In a recent study, Chuang et al., (2016) investigated the feasibiblity of using LESWs for
intravesical botulinum toxin A delivery. They evaluated the efficacy for acetic acid included
bladder hyperactivity in rats. They concluded that LESWs increased urothelial permeability,
facilitate intravesical botulinum toxin A delivery and block acetic acid included hyperactive
bladder. These results support LESWs as a promising method to deliver botulinum toxin A
without the need for injection.
Overactive bladder (OAB) is a condition characterized by presence of urinary urgency, usually
accompanied by frequency and nocturia, with or without urgency urinary incontinence [UUI], in
the absence of urinary tract infection (UTI) or other obvious pathology (Haylen BT et al
2010). OAB is a common problem that impair the quality of life (QOL).The prevalence of OAB
ranged from 11.8% in a population-based survey conducted across five European countries (
Irwin DE et al, 2008 ) to 16.9% according to Epidemiological studies from North America and
the prevalence increases with age rising to 30.9% in those over the age of 65 years.( Stewart
WF et al 2001) Treatment goals are to reduce the occurrence of bothersome symptoms, and
provide benefits that are perceived by patients as meaningful (Brubaker L et al, 2006).
Several treatment options are available for OAB including bladder and behavioral training ,
pharmacologic treatment , and surgical therapies (Wein AJ et al, 2006).
Antimuscarinics are well established as pharmacotherapy for reducing OAB symptoms and
improving QOL (Andersson KE et al, 2009). However, their use is limited in some patients by
insufficient response to treatment "refractory OAB", or intolerable side effects such as dry
mouth ,blurred vision, constipation, and cognitive impairment (Benner JS et al, 2010).
After a trial of pharmacotherapy, if the patient has not had an adequate improvement in
symptoms, intra-vesical injection of Botox (BTX) can be offered as the next step. Botulinum
toxin (BTX) is a neurotoxin, it contains a heavy chain that binds to the presynaptic terminal
of the neuromuscular junction , and this then acts by inhibiting the release of acetylcholine
from the presynaptic vesicles at the axon terminal of the motor end plate , that then result
in the muscle that is innervated becoming flaccidly paralyzed. BTX is available in different
preparations, each of which is a distinct chemical entity. The current commercially utilized
type is BTX type A.
Currently, there is cumulative data supporting use of BTX in cases of refractory Deturosr
overactivity. Intradetrusal injection of BTX is followed by a significant improvements in the
number of voiding episodes over 24 h, incontinence episodes, urodynamic variables and
quality-of -life scores (Mangera A et al, 2011). There is a reduction in episodes of urgency
and incontinence by 80% and 60%, respectively. The efficacy peaks at 4 weeks ,with the effect
lasting typically up to 9 months , and repeated treatment efficacy has been shown in up to 10
treatment cycles. Patients should be counseled about the risk of an increased postvoid
residual volume, occurring in 20-40% of individuals, and the need to use
self-catheterization, with the attendant risk of UTI (14-40%) (Mangera A et al, 2011). The
risk of general muscular weakness is considered very rare.
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