C. Lancaster

Gastric Antisecretory and Antiulcer Properties of PGE2, 15-Methyl PGE2, and 16,16-Dimethyl PGE2: Intravenous, oral and intrajejunal administration

15-Methyl PGE2 and 16,16-dimethyl PGE2 were found (1) to be 40 and 100 times, respectively, more potent than PGE2 after intravenous administration in inhibiting histamine-stimulated gastric secretion in dogs with a denervated (Heidenhain) gastric pouch, (2) to be active orally and intrajejunally, whereas PGE2 was inactive, and (3) to exert antisecretory activity for longer duration than PGE2. 16,16-Dimethyl PGE2 was about 2.5 times more potent than 15-methyl PGE2. Volume, acid concentration, and output, and pepsin output (but not concentration) were reduced in a dose-dependent manner. In the rat, 16,16-dimethyl PGE2 also inhibited gastric secretion and prevented the formation of ulcers produced by various methods: gastric ulcers (Shay, and steroid induced) and duodenal ulcers (secretogogue induced). In this species, 1l816-dimethyl PGE2 was 2 to 50 times more potent than PGE2, depending on the endpoint, and was active orally. These prostaglandins appear to inhibit gastric acid secretion by acting directly on the parietal cells, and making these unresponsive to most stimulants. Vomiting was a side effect of the prostaglandin analogues in the dog, but almost exclusively when these were given orally. After intravenous or intrajejunal administration at doses inhibiting gastric secretion by 80%, vomiting was seen only once. These results suggest that 15-methyl PGE2 and 16,16-dimethyl PGE2 may be of value in the treatment of peptic ulcer.

Cytoprotection by Prostaglandin Occurs in Spite of Penetration of Absolute Ethanol Into the Gastric Mucosa

Several prostaglandins are cytoprotective for the stomach; they prevent mucosal necrosis and hemorrhages produced by noxious agents, such as absolute ethanol. One possible mechanism of cytoprotection would be that the prostaglandin may prevent penetration of the necrotizing agent into the gastric mucosa. To test this hypothesis, 2 ml of 100% ethanol containing tracer amounts of 14C at carbon 1 was given orally to rats, after ligating the pylorus. [14C]Ethanol was measured in the gastric mucosa and in plasma from 2.5 to 60 min after ethanol administration. 16,16-Dimethyl prostaglandin E2 was given orally at a cytoprotective dose (10 micrograms/kg) 15 min before 100% ethanol. The level of [14C]ethanol (disintegrations per minute per gram of tissue) in the gastric mucosa of 16,16-dimethyl prostaglandin E2-treated animals were not different from those of control animals. The plasma levels were slightly lower during the first 10 min, but the area under the curve for the entire 60 min was the same in both groups. We conclude that (a) 16,16-dimethyl prostaglandin E2 does not prevent entry of ethanol into the gastric mucosa; (b) 16,16-dimethyl prostaglandin E2 protects the cells located deep in the gastric mucosa from necrosis, in spite of the fact that these cells are in contact with as much ethanol as cells of untreated animals; (c) gastric cytoprotection is probably due to a defense mechanism at the cellular level. These findings minimize the importance of luminal factors, such as an increase in mucus or bicarbonate, in the mechanism of cytoprotection.

Cysteamine-Induced Duodenal Ulcers: A New Model to Test Antiulcer Agents

Cysteamine, administered as a single subcutaneous or oral dose, produced duodenal ulcers in rats within 24 h. At least 50% of the ulcers perforated at a dose of 425 mg/kg subcutaneously. Cysteamine-in

Indomethacin-induced gastric antral ulcers in hamsters

Antral ulcers account for about half of gastric ulcers in humans. An animal model was developed to produce such ulcers. Indomethacin given subcutaneously to normally fed hamsters produced antral ulcers within 1-5 h, dose dependently. These ulcers penetrated the muscularis mucosae. With repeated administration of indomethacin and longer duration of treatment, the lesions became more severe and most animals died with perforated antral ulcers after 2-5 days. Like indomethacin, aspirin given orally also produced antral ulcers in hamsters. Indomethacin reduced the formation of prostaglandin E2, prostaglandin F2 alpha, and 6-keto prostaglandin F1 alpha by the antral mucosa, and increased gastric acid output more than twofold. The ulcers were prevented by various antisecretory agents (cimetidine, methscopolamine bromide, and omeprazole), and the antiulcer dose of each of these agents corresponded to the antisecretory dose. By contrast, several prostaglandins prevented the ulcers at very low, nonantisecretory doses. 16,16-Dimethyl prostaglandin E2 prevented the ulcers at a dose nearly 3000 times lower than the gastric antisecretory ED50. The mechanism by which prostaglandins prevent formation of these ulcers is unknown, but the effect is consistent with cytoprotection, i.e., protection of the gastric mucosa by nonantisecretory doses. Indomethacin-induced antral ulcers appear to depend on two factors: a depletion of prostaglandin content of the antrum and gastric hyperacidity.

Duodenal ulcers produced in rats by propionitrile: Factors inhibiting and aggravating such ulcers

Abstract Propionitrile (PPN), administered either sc or orally to female rats, produced within 2 days severe duodenal ulcers that often perforated. Such ulcers were prevented by methscopolamine bromide (an anticholinergic agent) and by 16,16-dimethyl prostaglandin E 2 (a gastric antisecretory agent). Overnight fasting and administration of prednisolone increased the toxicity of PPN, as shown by a high mortality rate, whereas desoxycorticosterone and ACTH did not influence the effects of PPN on ulcer formation and on toxicity. Male rats were found to be relatively resistant to PPN-induced duodenal ulcers. PPN had little effect on gastric secretion other than a moderate inhibition of pepsin secretion, but PPN retarded gastric emptying. Although the mode of action of PPN is unknown, the duodenal ulcers produced by this compound can be used as an assay for antiulcer agents.

Effect of 16, 16-dimethyl PGE2 on renal papillary necrosis and gastrointestinal ulcerations (gastric, duodenal, intestinal) produced in rats by mefenamic acid

Mefenamic acid, given orally to rats at a single dose of 1200 mg/kg, produced renal papillary necrosis (RPN) in 63% of animals. The incidence was reduced to 27% by 16,16-dimethyl PGE2 (dmPGE2), given at an oral dose of 0.75 mg/kg t.i.d. RPN is likely to be caused by the renal prostaglandin depletion elicited by mefenamic acid, an inhibitor of prostaglandin cyclooxygenase. Substitution with dmPGE2 reduces RPN presumably by preventing the prostaglandin depletion. We conclude that the prostaglandin used is cytoprotective for the kidney. Mefenamic acid, like most nonsteroidal anti-inflammatory compounds (NOSAC), produced ulcerations of the small intestine (jejunum and ileum). These were prevented by dmPGE2 (intestinal cytoprotection). Unlike most other NOSAC, however, mefenamic acid produced duodenal ulcers in nearly all animals (80%). Of these ulcers, 88% were perforated. Twenty-five of the twenty-six animals that died had a perforated ulcer. These duodenal ulcers were also prevented by dmPGE2. Mefenamic acid-induced ulcers could be used as an experimental model for testing agents with a potential for preventing or healing duodenal ulcers.

Prevention of cecitis in hamsters by certain prostaglandins

Acute inflammation of the colon (cecitis) was produced in hamsters by daily subcutaneous administration of an antibiotic for 3 days. The following prostaglandins completely prevented the cecitis: 16,16-dimethyl-PGE2, 15(R)-15-methyl-PGE2, and 2-acetyl-2-decarboxy-15(S)-15-methyl-PGF2 alpha. PGF2 beta was less active. The synthesis of 2-acetyl-2-decarboxy-15(S)-methyl-PGF2 alpha is described. Castor oil also prevented the cecitis and peanut oil exerted partial protection. Since these oils contain linoleic acid, a precursor of PGE1, protection may have been due to endogenous formation of that prostaglandin. A partial block of the protective effect of castor oil by treatment with indomethacin supports such mechanism. The tissue level of endogenous prostaglandins seems to exert protection since administration of cyclooxygenase inhibitors, indomethacin and aspirin, markedly increased the incidence of cecitis. Magnesium sulfate given orally and sodium salicylate given subcutaneously reduced the incidence of cecitis only partially. The following agents were inactive: loperamide, an antidiarrheic agent; carbachol, a cholinergic and diarrheogenic agent, atropine, an anticholinergic agent; and acetazolamide, a carbonic anhydrase inhibitor. These results, show that certain prostaglandins, which have been shown earlier to be cytoprotective for the stomach and the small intestine, are cytoprotective for the large intestine as well.

Effective Nonsteroidal Anti-Inflammatory Drugs Devoid of Gastrointestinal Side Effects: Do They Really Exist?

All nonsteroidal anti-inflammatory drugs (NSAIDs) cause gastrointestinal (GI) side effects. One focus of development was to design new drugs with reduced propensity for GI damage. With aspirin as the prototype, research efforts to develop NSAIDs with the efficacy but not the gastroduodenal damaging effects of aspirin have been partially successful. Techniques used to minimize gastric irritant potential include developing new drug classes, enteric coatings, nonacidic drugs, and prodrugs. Properties associated with the mucosal damaging effects of NSAIDs (potent inhibition of prostaglandin synthesis, solubility at low pH, and acid characteristic) are not found in the newer prodrugs such as droxicam and nabumetone. Droxicam was developed as a prodrug of piroxicam with equal efficacy, in addition to improved GI tolerance. Prodrugs may offer new molecules with pharmacological profiles and efficacy to toxicity ratios more acceptable to clinicians and patients alike.

Ulcer formation and cytoprotection by acetazolamine

Acetazolamide, a carbonic anhydrase inhibitor, was administered orally and subcutaneously to rats. Acetazolamide increased the gastric ulcerogenicity of indomethacin, but inhibited gastric ulcers produced by acidified aspirin. When administered alone to fasted rats, it did not produce gastric ulcers. Acetazolamide was also cytoprotective for the stomach (it reduced dose dependently the number of gastric necrotic lesions caused by absolute ethanol given orally) and for the small intestine (it prevented dose dependently intestinal lesions produced by administration of a high dose of indomethacin). Acetazolamide did not prevent the antiulcer effect of PGE2 (against aspirin-induced ulcers) nor the cytoprotective effect of 16,16-dimethyl PGE2 (against ethanol-induced gastric lesions). The degree of gastric cytoprotection increased with time after a single administration of acetazolamide; the optimal effect occurred 60 and 90 min after oral and subcutaneous administration, respectively. Pretreatment with indomethacin completely prevented the cytoprotective effect of acetazolamide; this suggests that the cytoprotective effect may be mediated by endogenous release of prostaglandins by the stomach. All the effects of acetazolamide reported here were observed after either oral or subcutaneous administration. The mechanism by which acetazolamide influences ulcer formation and is cytoprotective is unknown.

Duodenal ulcers produced in rats by indomethacin plus bile duct ligation

Duodenal ulcers were produced in rats by ligating the common bile and giving indomethacin immediately after. Neither indomethacin alone nor bile duct ligation alone was ulcerogenic. When the two conditions were combined, the ulcers developed within 24 hours and began to perforate after 48 hours. No gastric ulcers were performed. The incidence of duodenal ulcers and perforations increased with the dose of indomethacin. The optimal conditions were: fed animals given a single administration of 10– 20 mg/kg of indomethacin orally or subcutaneously, given after bile duct ligation, and killed two days later. The ulcers were prevented by antisecretory agents (methscopo- lamine bromide, 16,16-dimethyl PGE2 at a subcutaneous antisecretory dose) and an antacid, as well as by 16,16-dimethyl PGE2 given orally at a non-antisecretory dose (cytoprotection). The mechanism by which indomethacin plus bile duct ligation is duodeno-ulcerogenic appears to involve reduction of bicarbonate in duodenal contents due to lack of alkaline bile (from bile duct ligation) and to inhibition of bicarbonate secretion by the duodenal mucosa (an effect of indomethacin). Reduction of prostaglandin content of the duodenal mucosa, by indomethacin administration, may sensitize the mucosa to the damaging effect of unbuffered gastric acid.