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BASIC
AND TRANSLATIONAL UROLOGY
Urodynamic
and immunohistochemical evaluation of intravesical botulinum toxin A delivery
using liposomes
Chuang YC, Tyagi P, Huang CC, Yoshimura N, Wu M, Kaufman J, Chancellor
MB
Department of Urology, Chang Gung Memorial Hospital, Kaohsiung Medical
Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan,
Republic of China
J Urol. 2009; 182: 786-92
- Purpose:
Botulinum toxin A (Allergan, Irvine, California) is a high molecular
weight neurotoxin used to treat hypersensitive bladder by direct injection
to pass the urothelial barrier. We investigated the feasibility of
intravesical botulinum toxin A delivery using liposomes (Lipella Pharmaceuticals,
Pittsburgh, Pennsylvania), which are phospholipid bilayered vesicles,
and evaluated the urodynamic and immunohistochemical effect on acetic
acid induced bladder hyperactivity in rats.
Materials and Methods: Liposomes (1 ml), botulinum toxin A (20 U/1
ml saline) or botulinum toxin A encapsulated in liposomes (lipotoxin,
that is 20 U botulinum toxin A plus 1 ml liposomes) was administered
in the bladder and retained for 1 hour on day 1 after baseline cystometrogram.
Continuous cystometrogram was performed on day 1 by filling the bladder
with saline and on day 8 by filling the bladder with saline, followed
by 0.3% acetic acid. The bladder was then harvested. Cystometrogram
parameters, histology, SNAP25 and calcitonin gene-related peptide
expression were measured by Western blotting or immunostaining.
Results: The intercontraction interval was decreased 57.2% and 56.0%
after intravesical acetic acid instillation in liposome and botulinum
toxin A pretreated rats, respectively. However, rats that received
lipotoxin showed a significantly decreased intercontraction interval
response (21.1% decrease) to acetic acid instillation but without
compromised voiding function. Also, lipotoxin pretreated rats had
a better decrease in the inflammatory reaction and SNAP-25 expression,
and increase in calcitonin gene-related peptide immunoreactivity than
those in liposome or botulinum toxin A pretreated rats.
Conclusions: Intravesical lipotoxin administration cleaved SNAP-25,
inhibited calcitonin gene-related peptide release from afferent nerve
terminals and blocked the acetic acid induced hyperactive bladder.
These results support liposomes as an efficient vehicle for delivering
botulinum toxin A without injection.
- Editorial
Comment
It has been proved that Botulinum toxin A applied as cystoscopic guided
injections into the bladder wall have a therapeutic effect on overactive
bladder and interstitial cystitis / painful bladder syndrome. Nevertheless,
we know well that bladder injection therapy has some limitations,
including drug leakage outside the bladder, hematuria, pain at injection
sites and uneven distribution. In this way, the authors have been
searching for a simpler and lower risk method to deliver Botulinum
toxin A without injection.
We know that it is difficult for Botulinum toxin A to access the submucosal
nerve plexus in formal use with saline as a vehicle without direct
injection to pass the urothelial barrier. Based on previous experience,
the authors speculated that delivery using liposomes, which are phospholipid
bilayered vesicles, and evaluated the urodynamic and immunohistochemical
effect on acetic acid induced bladder hyperactivity in rats.
Their results show that Botulinum toxin A can be combined with liposomes
to be administered as a liquid instillation without cystoscopic injection,
with good therapeutic results in rats.
To our knowledge, this is the first report of the promise of liquid
instillation of Botulinum toxin A. I strong recommend this paper to
all physicians involved in research on neurourology.
Dr.
Francisco J. B. Sampaio
Full-Professor and Chair, Urogenital Research Unit
State University of Rio de Janeiro
Rio de Janeiro, RJ, Brazil
E-mail: sampaio@urogenitalresearch.org
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