| dc.contributor.author | Raoul, Jennifer M. | en_US |
| dc.date.accessioned | 2014-10-21T12:36:50Z | |
| dc.date.available | 2004 | |
| dc.date.issued | 2004 | en_US |
| dc.identifier.other | AAINQ94050 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54665 | |
| dc.description | Crohn's disease (CD) is a chronic relapsing and remitting inflammatory bowel disease characterized by transmural granulomatous inflammation and ulceration with development of intestinal fibrosis and strictures. Current treatments for CD target acute symptoms but do little to prevent fibrotic complications of the disease. Our lab has been investigating the antifibrogenic effects of pentoxifylline (PTX), a methylxanthine derivative with known anti-inflammatory actions. We have previously shown that PTX inhibits fibrogenic events in vitro and in a swine model of hepatic fibrosis. The combined antifibrogenic and anti-inflammatory effects of PTX make it an attractive candidate for the treatment of human CD. We have developed a method to produce a racemic mixture of the chiral metabolite-1 (M-1) of PTX and this thesis work was an examination of the antifibrogenic and anti-inflammatory effects of M-1 in vitro and in an animal model of CD. M-1 was more potent than PTX in vitro at inhibiting platelet-derived growth factor (PDGF)-stimulated fibroblast proliferation and collagen synthesis, hallmark events in fibrosis. Kinetics of M-1 showed that higher levels of total active drug were achieved in vivo following M-1 administration compared to PTX. A pharmacologic interaction between M-1 and the antibiotic ciprofloxacin was demonstrated that may enhance the biological effects of M-1 in vivo. Both PTX and M-1 attenuated inflammation and colon damage in the TNBS rat model of colitis when administered intracolonically. Antiinflammatory actions of PTX and M-1 in vivo are likely due to inhibition of NF-kappaB, which was significantly elevated in colitis. Intestinal fibrosis in the model was characterized by elevated levels of collagen types I and III and PDGF in colon tissue. Only M-1 prevented intestinal fibrosis in this model of colitis. These results suggest that PTX and M-1 could have therapeutic potential in the treatment of inflammation and ulceration associated with human CD. M-1 may also inhibit inflammation-induced intestinal fibrosis in CD, for which there is currently no treatment. This is the first study to examine the effects of M-1 in vivo and one of the only studies to examine the effects of pharmacological agents on fibrosis in an experimental model of IBD. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2004. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.subject | Health Sciences, Pathology. | en_US |
| dc.title | Effects of a novel metabolite of pentoxifylline in vitro and in vivo in models of fibrosis and inflammation. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
