rioprostil and Chronic-Disease

Rioprostil, a primary alcohol prostaglandin E1 analog, inhibits gastric acid secretion and prevents gastric lesions induced by a variety of irritants in experimental animals. Because rioprostil is relatively short-acting, it would be of significant benefit clinically if its duration of action could be extended to allow once daily dosing. This investigation demonstrates that when administered via an osmotically driven pump (Osmet, Alza Corp.), rioprostil prevents the acute effects of aspirin on the gastric mucosa of dogs, accelerates the healing of aspirin-induced gastric lesions, and heals preexisting aspirin-induced gastric lesions during chronic administration of aspiring. The potency of rioprostil against acute gastric lesion formation was greatest when delivered from a 24-hr release pump (ED50 = 0.77 micrograms/kg/24 hr) and was 37 times greater than when administered as a single oral bolus. In addition, this activity occurred at doses which had little or no gastric antisecretory activity in betazole-stimulated Heidenhain pouch dogs. When delivered from a 24-hr pump, rioprostil (100 micrograms/kg/24 hr) healed preexisting aspirin-induced gastric lesions within 8 days after removal of aspirin, or after 15 days during continued daily aspirin administration. Additional studies determined that administration of rioprostil at doses of 720, 1440, or 2160 micrograms/kg/24 hr (935-2805 times the gastroprotective ED50 in 24 hr pumps) was well tolerated, with only slight, transient increases in body temperature, softening of the stools, and mild sedation at the highest dose. Administration of rioprostil daily for 5 days at 960 micrograms/kg/24 hr from 24-hr release pumps was also well tolerated by all dogs with no evidence of any accumulation of effect of rioprostil. In summary, administration of rioprostil via an osmotic pump increases its potency and duration of action against the gastric lesion-inducing effect of aspirin, and maintains a wide ratio of safety.

Topics: Acute Disease; Administration, Oral; Animals; Anti-Ulcer Agents; Aspirin; Chronic Disease; Dogs; Female; Gastric Juice; Infusion Pumps; Male; Prostaglandins E; Rioprostil; Stomach Ulcer

The role of leukotrienes in the pathogenesis of chronic colitis was investigated using a rat model. Ulceration and inflammation of the distal colon was initiated by the intracolonic administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Leukotriene B4 synthesis increased significantly within 4 h after induction of damage, with the greatest increase observed 24-72 h after administration of the hapten. The increase in leukotriene B4 synthesis correlated well (r = 0.88) with an increase in colonic myeloperoxidase activity, a biochemical marker of neutrophil infiltration. Daily intracolonic treatment with a specific 5-lipoxygenase inhibitor, L651,392, during the first 4 days after initiation of colitis, resulted in significant reductions of colonic leukotriene B4 synthesis, colonic damage score, and colon wet weight. When examined 2 wk after initiation of colitis, the group treated with L651,392 (for the first 4 days) showed significantly less colonic damage (assessed macroscopically and histologically) and colonic inflammation (assessed histologically and by measurement of myeloperoxidase activity). The healing produced by treatment with L651,392 was comparable to that observed after treatment with 5-aminosalicylic acid in a similar manner. Although a reduction of colonic damage could be produced in this model by intracolonic pretreatment with a prostaglandin E1 analogue (rioprostil), the mechanism of action of L651,392 did not appear to be through prevention of the initial injury induced by the hapten and ethanol solution. These results demonstrate that inhibition of leukotriene synthesis results in a marked acceleration of the healing of colonic ulcers and resolution of colonic inflammation in this animal model of chronic colitis. The results are therefore consistent with the hypothesis that leukotrienes play an important role in the pathogenesis of intestinal inflammation.

Topics: 6-Ketoprostaglandin F1 alpha; Aminosalicylic Acids; Animals; Chronic Disease; Colitis; Colon; Leukotriene B4; Lipoxygenase Inhibitors; Male; Mesalamine; Peroxidase; Phenothiazines; Prostaglandins E; Rats; Rats, Inbred Strains; Rioprostil