Effects of Dexamethasone or Celecoxib on Biliary Toxicity after Hepatic Arterial Infusion of 5-Fluorodeoxyuridine in a Canine Model

Abstract

Previous work has shown that in humans the dose-limiting toxicity for fluorodeoxyuridine [2-fluoro-5-deoxyuridine (FdUrd)] when administered by hepatic arterial infusion is biliary sclerosis. The current study was undertaken to attempt to modify this toxicity in a canine model that has been demonstrated to closely mimic the clinical situation. Unlike previous studies using this model, in which animals were sacrificed after extensive fibrosis had already occurred, the current experiments were designed so that observations of pathology were made at an earlier time, when the initial inflammatory injury underlying the fibrotic process was still taking place. Implantable pumps were used to deliver FdUrd into the hepatic artery of animals at a rate of 0.3 mg/kg/day in the presence or absence of 10 mg/week dexamethasone or 100 mg/day of celecoxib for 35 days, at which time the animals were beginning to show signs of toxicity. After evaluation for radiological evidence of biliary obstruction, the animals were sacrificed and portions of their livers were processed for examination of microscopic pathology and 2-bromo-5deoxyuridine labeling index. Dexamethasone treatment protected the animals from biliary sclerosis determined radiologically, further validating this model as being representative of the response in humans. Similarly the Cox-2 inhibitor, celecoxib, appeared to provide protection against radiological changes of biliary stricture, although possibly to a lesser degree than the resultant from dexamethasone. In addition, FdUrd treatment caused elevation of the DNA 2-bromo-5deoxyuridine labeling index above control levels in biliary epithelial cells. Dexamethasone and celecoxib each significantly attenuated the FdUrd-induced elevation of DNA labeling index in biliary epithelium. These findings demonstrate the usefulness of this canine model for studying the mechanisms of drug-induced biliary sclerosis and reinforce the hypothesis that blocking inflammation may retard the progression of injury that eventually leads to fibrosis. This study suggests that clinical testing of celecoxib as a preventive for hepatic arterial-FdUrd induced biliary damage could prove valuable.

Precision-cut fibrotic rat liver slices as a new model to test the effects of anti-fibrotic drugs in vitro

“…In vivo, anti-fibrotic effects of dexamethasone were observed in a model for biliary sclerosis [26] and in a schistosomiasis model [27], which was attributed to its anti-inflammatory effects. In contrast, dexamethasone was ineffective in inhibiting established dimethylnitrosamine-induced fibrosis [28].…”

Função renal, hepática e cardíaca de cães hígidos sob terapia prolongada com celecoxibe

“…No homem, o aspecto clínico dessa lesão varia desde elevações assintomáticas das aminotransferases até quadros de hepatite aguda grave com icterícia hepatocelular, evoluindo para óbito (BARBOSA, 2008). Em contrapartida, ENSMINGER et al (2004) referem que o uso de celecoxibe em cães submetidos a contraste tóxico para as vias biliares foi capaz de reduzir as injúrias induzidas pelo contraste, tais como necrose e esclerose.…”

“…Ademais, a COX-2 atua no rim e a administração de drogas seletivas para COX-2 pode afetar adversamente o órgão em condições de desidratação, diminuição da perfusão ou doença renal. Por outro lado, com o uso de fármacos desta classe há favorável tolerabilidade gastrintestinal (PAPICH, 2008) e hepática (ENSMINGER et al, 2004). Na medicina veterinária, em especial em pequenos animais, há carência de protocolos terapêuticos que padronizem o uso de inibidores COX-2 (ALENCAR et al, 2003).…”

Hilar Biliary Obstruction: Malignant Masquerades

“…[10][11][12] Concomitant infusion of dexamethasone or systemic therapy with the COX-2 inhibitor celecoxib decreases but does not eliminate the incidence of CIBS. 13,14 Although cessation of pump chemotherapy may normalize hyperbilirubinemia, some patients require biliary drainage by endoscopic or percutaneous techniques.…”