SENO Toshinobu Okayama University, Medical School Assiatant, 医学部, 助手 (70127562)
MATSUMOTO Shuji Okayama University, Medical School Assiatant, 医学部, 助手 (60209632)
OCHI Koji Okayama University, Medical School Assistant, 医学部附属病院, 助手 (60160884)
TANAKA Juntaro Okayama University, Medical School Lecturer, 医学部附属病院, 講師 (00116477)
|Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 1991: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1990: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1989: ¥800,000 (Direct Cost: ¥800,000)
We have demonstrated that the levels of prostaglandins(PGs)and thromboxane(TX)are elevated in pure pancreatic juice from patients with pancreatitis. The findings led us to investigate the role of PGs and TX in the pathophysiology and treatment of pancreatitis.
1. Basic investigations :
Preliminary studies showed that caerulein-induced pancreatitis in rats is most suitable for the study and that caerulein(Cn)(Sigma, St. Louis, USA)10 ug/kg should be injected subcutaneously four times at 1-hour intervals to be sacrificed at 6 hours for quantitating pancreas weight, ascites, serum pancreatic enzymes, and histologic evidence of damage. In the second experiment, effects of 16, 16-dimethyl PGE2(dmPGE2)or indomethacin(IND)on pancreatitis were determined. dmPGE2(10, 30 or 100 ug/kg)was injected subcutaneously twice(30 min before and 3 hours after the start of Cn injection), once 30 min before, or once 30 min after the start of Cn injection. Indomethacin(IND)(Sigma, St. Louis, USA)5 mg/kg was inj
ected subcutaneously 1 hour before and 3 hours after the start of Cn injection. In the third experiment, effects of dmPGE2 or IND on pancreatic content of endogenous PGs and TXB2 were evaluated. Based on a preliminary study. Cn 10 ug/kg was injected twice and rats were killed at 2 hours. dmPGE2 100 ug/kg or IND 5 mg/kg was injected 30 min before the start of Cn-injection. The Cn dosage induced edematous pancreatitis(edema, vacuoles, cell infiltration)without necrosis. dmPGE2 induced dose- and time-dependent improvements in the severity of pancreatitis. A combination of pre- and post-treatment with dmPGE2 induced a marked improvement, whereas either pre- or post-treatment alone induced only a mild improvement. In contrast, IND exerted deleterious effects on the above parameters with appearance of pancreatic necrosis. Cn-induced pancreatitis showed a marked increase in endogenous PGE2, 6-koto-PGF1a, TXB2 and 6-keto-PGF1a/TXB2 ratio. IND and dmPGE2 administration induced a marked decrease in PGE2.6-keto-PGF1a, TXB2, 6-keto-PGF1a/TXB2 ratio and PGE2/TXB2 ratio. In dmPGE2-treated rats, the decrease of endogenous PGE2 was wellcompensated for by exogenous dmPGE2 ; however, the decreased 6-keto-PGF1a/TXB2 ratio was considered to carry a potential risk of deteriorating pancreatitis, depending on pancreatitis models. In IND-treated rats, in contrast, the decreased 6-keto-PGF1a and 6-keto-PGF1a/TXB2 ratio was considered to induce deterioration with pancreatic necrosis in the setting of decreased PGE2 and PGE2/TXB2 ratio.
2. Clinical studies :
Characteristic findings in pure pancreatic juice from patients with pancreatitis were raised levels of TXB2 and TXB2/6-keto-PGF1a ratio on clinical exacerbations and restorations towards normal on clinical improvements. Indomethacin at doses given in clinical practice induced neither clinical exacerbations nor significant decreases in PGE2/TXB2 ratio and 6-keto-PGF1a/TXB2 ratio.
In conclusion, PGE2 gives a protective effect on pancreatitis in rats. However, clinical use of exogenous PGE2 for the therapy of pancreatitis is not presently justified because of insufficient efficacy of PGE2 given after the onset of pancreatitis and a potential risk of a decreased 6-keto-PGF1a/TXB2 ratio. Indomethacin frequently used for pain relief should be prescribed cautiously because of a potential risk of deteriorating pancreatitis through a decrease in endogenous 6keto-PGF1a, 6-keto-PGF1a/TXB2 ratio. PGE2. and PGE2/TXB2 ratio. Less