title: Urodynamic and Immunohistochemical Evaluation of Intravesical Botulinum Toxin A Delivery Using Low Energy Shock Waves.
abstract: OBJECTIVE
  We investigated the feasibility of using low energy shock waves for intravesical botulinum toxin A delivery. We also evaluated its efficacy for acetic acid induced bladder hyperactivity in rats.
  
  
  METHODS
  In study 1 magnetic resonance imaging with intravesical administration of Gd-DTPA (Gd-diethylenetriamine pentaacetic acid) contrast medium was performed to visualize increased bladder urothelial permeability after low energy shock waves. In study 2 saline (1 ml) or botulinum toxin A (20 U/1 ml saline) was administered in the bladder with or without low energy shock waves (300 pulses at 0.12 mJ/mm(2)) and retained for 1 hour on day 1. Continuous cystometrograms were performed on day 8 by filling the bladder with saline followed by 0.3% acetic acid. The bladder was harvested for histology, and SNAP-25, SNAP-23 and COX-2 expression by Western blot or immunostaining.
  
  
  RESULTS
  Magnetic resonance imaging established bladder urothelial leakage of Gd-DTPA after low energy shock waves, which was not seen in controls. The intercontraction interval was decreased 71.9%, 72.6% and 70.6% after intravesical instillation of acetic acid in saline, saline plus low energy shock wave and botulinum toxin A pretreated rats, respectively. However, rats that received botulinum toxin A plus low energy shock waves showed a significantly reduced response (48.6% decreased intercontraction interval) to acetic acid instillation without compromising voiding function. Rats pretreated with botulinum toxin A plus low energy shock waves showed a decreased inflammatory reaction (p <0.05), and decreased expression of SNAP-23 (p <0.05), SNAP-25 (p = 0.061) and COX-2 (p <0.05) compared with the control group.
  
  
  CONCLUSIONS
  Low energy shock waves increased urothelial permeability, facilitated intravesical botulinum toxin A delivery and blocked acetic acid induced hyperactive bladder. These results support low energy shock waves as a promising method to deliver botulinum toxin A without the need for injection.
authors.affiliation: Department of Urology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China; Institute of Medicine, Chung Shan Medical University, Taiwan, Republic of China. Electronic address: chuang82@ms26.hinet.net.
authors.forename: Yao-Chi
authors.initials: YC
authors.lastname: Chuang
authors.affiliation: Department of Radiology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China.
authors.forename: Tung-Liang
authors.initials: TL
authors.lastname: Huang
authors.affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Tyagi
authors.affiliation: Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Kaohsiung, Taiwan, Republic of China.
authors.forename: Chao-Cheng
authors.initials: CC
authors.lastname: Huang
mesh_terms: D000283:Administration, Intravesical; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005260:Female; D007150:Immunohistochemistry; D009465:Neuromuscular Agents / Q000008:administration & dosage* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D001743:Urinary Bladder / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D053201:Urinary Bladder, Overactive / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D014563:Urodynamics / Q000187:drug effects
chemical_list: D015415:Biomarkers; D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A
keywords: botulinum toxins; drug delivery; permeability; urinary bladder; urothelium