Chuang Y C1, Tyagi P2, Huang C C3, Yoshimura N4, Wu M1, Kaufmann J5, Chancellor M2 1. Chang Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung University College of Medicine,
Kaohsiung, Taiwan,, 2. William Beaumont Hospital, 3. Pathology Department, Chang Gung Memorial Hospital,
Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan,, 4. University of
Pittsburgh, 5. Lipella Pharmaceuticals, Inc., Pittsburgh, PA INTRAVESICAL
CYCLOPHOSPHAMIDE INDUCED OVERACTIVE BLADDER
Hypothesis / aims of study
Potent immunosuppressive effect of FK506 (
tacrolimus) has encouraged its topical application for achieving local anti-
inflammatory effect. However, its poor aqueous solubility presents challenges in formulating safe, biocompatible instillations for
bladder. The present study investigated the feasibility of tacrolimus delivery using liposomes for intravesical
Study design, materials and methods
Adult female Sprague-Dawley rats( 52) divided into 4 experimental groups were injected with CYP (200 mg/kg, ip) except for
sham (saline injection, ip). Other three groups received either saline (1 cc, retained for 1 hr), liposome (LP- 1 cc) or liposomal
encapsulated tacrolimus (LFK- 0.2mg tacrolimus/1 ml LP) by intravesical route. Baseline cystometrogram was performed in all
the experimental groups except in sham on day 1 before any treatment and on day 3 prior to bladder harvest for histological
staining (N=24). In addition, 4-hr baseline urine on day 1 and day 3 was also collected from all experimental groups for urine
PGE2 assay and bladder harvested for PGE2 and IL2 assay on day 3 (N=28).
CYP induced bladder inflammation was associated with increased EP4 staining, and bladder overactivity (intercontraction
interval 61.0% decrease). In addition, bladder PGE2 and IL2 level were both elevated 3.5 fold and urine PGE2 was increased
by 13.8 fold. Rats pretreated with LFK demonstrated suppression of CYP induced inflammatory reaction as revealed by
reduced EP4 staining, bladder overactivity and normalized IL 2 and PGE2 levels in tissue and urine. Intravesical LPs
pretreatment had no effects on uninjured rat bladder and did not suppress CYP effects.
Interpretation of results
LFK significantly inhibited CYP induced inflammation through the modulation of IL2, PGE2, and EP4 function. These findings
support investigation of local LFK for refractory overactive bladder.
This is the first report of intravesical immunesuppression in bladder by delivery of tacrolimus using liposomes.
1. Tamura S, Ohike A, Ibuki R, Amidon GL, Yamashita S (2002). Tacrolimus is a class II low-solubility high-permeability drug:
the effect of P-glycoprotein efflux on regional permeability of tacrolimus in rats. J Pharm Sci.91: 719-29.
2. Inagaki N, Shiraishi N, Igeta K, Nagao M, Kim JF, Chikumoto T, Itoh T, Katoh H, Tanaka H, Nagai H. Depletion of
substance P, a mechanism for inhibition of mouse scratching behavior by tacrolimus.Eur J Pharmacol. 2010 25;626(2-3):283-9.
3. Chuang YC, Yoshimura N, Huang CC, Wu M, Chiang PH, and Chancellor MB. Intravesical Botulinum Toxin A
Administration Inhibits COX-2 and EP4 Expression and
Specify source of funding or grant
Is this a clinical trial?
What were the subjects in the study?
Were guidelines for care and use of laboratory animals followed
or ethical committee approval obtained?
Name of ethics committee
Institutional Animal Care and Use Committee,Kaohsiung Medical
Detailed instructions: references (‘Vancouver’ style) References should be numbered consecutively in the order in which they are first mentioned in the text. Identify references in text, tables, and legends by superscript Arabic numerals. The experiment by Abbot was inconclusive.1 Work by Friedel and Schmidt suggests that the Multiple sources may be cited at a single point in the text.
Resolución N° CD-SIBOIF-618-2-MAR9-2010 De fecha 09 de marzo de 2010 NORMA SOBRE ORGANIZACIÓN Y FUNCIONAMIENTO DEL REGISTRO DE VALORES DE LA SUPERINTENDENCIA DE BANCOS Y DE OTRAS INSTITUCIONES FINANCIERAS El Consejo Directivo de la Superintendencia de Bancos y de Otras Instituciones Financieras. CONSIDERANDO Que el artículo 7, de la Ley No. 587, ¨ Ley de Mercado de C