The effects of high-dose ibuprofen and pancreatic enzymes on the intestine of the rat.
BACKGROUND
High-dose ibuprofen therapy limits the progression of lung disease in patients with cystic fibrosis. However, ibuprofen increases intestinal permeability, which potentiates intestinal damage caused by high-dose pancreatic enzyme treatment, as was shown in a previous study by this group. In the present study, the combined effects of ibuprofen and pancreatic enzyme treatment on the intestine and liver were examined.


METHODS
Using a chronically catheterized rat model, high-dose ibuprofen (60 mg/kg x day in two doses), with or without pancreatic enzyme treatment was infused into gastric and duodenal catheters, respectively, for 20 days. Six groups were studied: control group; ibuprofen treatment alone; pancreatic enzyme treatment alone (two groups: normal dose, 10,000 U lipase/kg x day and high dose, 40,000 U lipase/kg x day); and ibuprofen combined with pancreatic enzyme (two groups: ibuprofen with high-dose pancreatic enzyme and ibuprofen and low-dose pancreatic enzyme). After treatment, rats were autopsied, and complete histologic analyses of the entire intestine and liver were performed.


RESULTS
Ibuprofen caused mild ulceration of the small intestine in 50% of rats. Pancreatic enzyme treatment alone did not induce ulceration of the intestine. The combination of pancreatic enzyme and ibuprofen treatment increased the severity of the ulcers in the small intestine but not the number of ulcers or the percentage of rats affected. Ibuprofen treatment alone did not cause ulcers in the large intestine, but with the addition of pancreatic enzymes, ulceration and fibrosis were present.


CONCLUSIONS
Ibuprofen at doses used to limit progression of cystic fibrosis lung disease caused enteropathy in 50% of rats. There was synergism between ibuprofen and pancreatic enzyme treatment in the production of severe ulcers. Ulcers in the cecum and colon were increased with combined ibuprofen and pancreatic enzyme treatment compared with incidence in control animals.
Kimura
R E
RE
Department of Pediatrics, Rush Medical College, Chicago, Illinois, USA.
Dy
S A
SA
Uhing
M R
MR
Beno
D W
DW
Jiyamapa
V A
VA
Lloyd-Still
J D
JD
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D007052:Ibuprofen / Q000008:administration & dosage / Q000633:toxicity*; D007410:Intestinal Diseases / Q000139:chemically induced* / Q000145:classification; D007421:Intestine, Small / Q000187:drug effects* / Q000473:pathology; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D008297:Male; D010194:Pancreatin / Q000008:administration & dosage / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D014456:Ulcer / Q000139:chemically induced* / Q000473:pathology
D010194:Pancreatin; D007052:Ibuprofen