Leaf Huang Ph.D.
INTRAVESICAL THERAPY OF INTERSTITIAL CYSTITIS
Pradeep Tyagi, Ph.D.
University of Pittsburgh, April 4th, 2005
Interstitial cystitis (IC) is an inflammatory disorder of bladder which affects middle-aged Caucasian women. Intravesical administration of drugs is a mainstay in its treatment either as adjunct to oral therapy or as second-line therapy. The vehicles currently used for this route of administration are ideally suited for hydrophobic drugs and typically maintain drug exposure in the bladder for very short duration of time. The present dissertation project was aimed at investigating the use of alternative vehicles for improving intravesical drug delivery of hydrophobic small molecular weight drugs such as capsaicin misoprostol in addition to the delivery of large molecular weight peptide nucleic acid (PNA) for antisense based therapy. The hydrophobic drugs selected for this study were delivered by intravesical route using liposomes, thermosensitive hydrogel and TAT peptide. The efficiency of drug delivery was assessed by measuring the physiological response of normal and diseased rat bladder by metabolic cages and the method of cystometrogram (CMG). Histology and immunohistochemistry of bladder and spinal cord sections was done to corroborate the response measured in the physiological measurement. Liposomes were demonstrated to be a superior vehicle for capsaicin and thermosensitive hydrogel was able to sustain the exposure of a hydrophobic drug in the bladder for prolonged time and increase the efficacy of misoprostol in rat model of cystitis induced by cyclophosphamide. An interesting observation made during the study was that liposomes in absence of drug were able to modulate physiological response of bladder and this observation was further investigated to define the charge on the lipid headgroup and the structural requirements of hydrophobic backbone in the lipids for reducing bladder hyperactivity induced by sequential infusion of protamine sulfate and high concentration of KCl. Overexpression of NGF in cyclophosphamide induced cystitis was downregulated in the urothelium of rat bladder using antisense based therapy with PNA, which was delivered with the aid of TAT peptide. Overall, the study concluded that liposomes cannot only be a treatment option but can also be used for delivery of hydrophobic drugs. The potential of hydrogels and cell penetrating peptides for intravesical drug delivery needs further investigation.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04082005-122138 |
| Date | 20 May 2005 |
| Creators | Tyagi, Pradeep |
| Contributors | Song Li, Dexi Liu, Billy Day, Leaf Huang, Michael Chancellor |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04082005-122138/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
Page generated in 0.0025 seconds