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Enprostil, a synthetic prostaglandin E2 analogue, inhibits meal-stimulated gastric acid secretion and gastrin release in patients with duodenal ulcer
Enprostil, a Synthetic Prostaglandin E2 Analogue, Inhibits Meal-Stimulated Gastric Acid Secretion and Gastrin Release in Patients with Duodenal Ulcer
FRANK J. THOMAS, M.D. MICHAEL A. KO.SS, B.S. DANIEL L. HOGAN, B.A. JON I. ISENBERG, M.D. San Diego, California
Fromthe Divisionof Gastroenterology,Department of Medicine, UCSD Medical Center, Universityof California, San Diego, san Diego, California. This work was supported by a grant from Syntex Research, PaloAlto, California. Requestsfor reprints should be addressed to Dr. Jon I. Isenberg, Division of Gastroenterology, UCSD Medical Center (H-81l-D), 225 Dickinson Street, San Diego, California 92103.
44
The effect of enprostil, a synthetic dehydro-prostaglandin E2, on meal-stimulated gastric acid secretion and gastrin release was studied in six patients with inactive duodenal ulcer disease. Each subject underwent seven tests in random order on separate days: placebo intragastrically and intraduodenally; enprosti135 and 70 pg both intragastrically and intraduodenally; and ranitidine 150 mg intragastrically. After measuring basal gastric acid secretion and gastrin release, a liquid meal (500 ml, pH 5.5, 40 g protein, 30 g fatl 30 g carbohydrate, 550 Kcal, 768 mOsm) was given. Gastric acid secretion and gastrin release were measured over the next four hours. A second identical meal was instilled and both parameters were measured for an additional four hours. Thirty-five and 70 pg of enprostil administered intragastrically reduced total eight-hour gastric acid secretion by 58 percent and 82 percent, respectively (p <0.05). The 35 and 70/~g doses administered intraduodenally decreased gastric acid secretion by 67 percent and 91 percent, respectively (p <0.05 compared with placebo). Ranitidine suppressed gastric acid secretion by 95 percent, which was similar to the suppression achieved with the 70/xg dose of enprostil. The total mealstimulated integrated gastrin response was significantly suppressed by both intragastric doses of enprostil and by the 70 pg dose given intraduodenally (p <0.05). Compared with placebo, the 35 /xg intragastric and intraduodenal doses decreased the integrated gastrin response by 73 percent and 72 percent, respectively. The 70 pg intragastric and intraduodenal doses of enprostil reduced the integrated gastrin response by 90 percent and 125 percent, respectively. Ranitidine did not alter the integrated gastrin response. It is concluded that enprostil significantly inhibited both mealstimulated gastric acid secretion and gastrin release. The response to enprostil occurred in a dose-dependent manner and was similar regardless of the route of administration. Prostaglandins of the E class are potent inhibitors of gastric acid secretion [1-12]. Synthetic analogues of prostaglandin E are more effective than natural prostraglandin E in decreasing acid secretion [1]. Most, but not all, of the synthetic analogues of prostaglandin E2 are more effective inhibitors of gastric acid secretion when administered directly into the stomach rather than into the duodenum [3,12]o Enprostil, a synthetic dehydro-prostaglandin E2, also suppresses gastric acid secretion [8]. This study was undertaken to assess the effect of enprostil on meal-stimulated acid secretion and gastrin release in patients with inactive duodenal
August18, 1986 The American Journal of Medicine Volume81 (suppl 2A)
SYMPOSIUMON GASTROINTESTINALPROSTAGLANDINS--THOMASET AL
TABLE I
Mean (•
Gastric Acid Secretion First Meal (retool/4 hours)
Second Meal (mnlol/4 hours)
Total (mrno[/8 hours)
Intragastric Placebo Enprostil (35/~g) Enprostil (70 #g) Ranitidine (150 mg)
65.2 • 20.1 15.3 -+-5.6* 4.5 • 2.8*t 2.4 • 1.7"
48.6 • 14.2 26.1 --- 10.0 15.0 • 5.2* 5.2 • 3.2*
113.8 - 33.8 43.1 • 14.9~ 19.4 +-- 11.7"t 7.6 --- 4.3*
Intraduodenal Placebo Enprostil (35/~g) Enprostil (70/~g)
60.2 -'- 18.3 13.9 • 6.0" 4.0 • 1.3"
53.4 - 20.2 30.8 • 10.4 7.8 • 4.4 ~
113.6 • 38.0 44.7 -'- 15.7" 11.8 • 5.4*t
*p <0.05 compared with placebo. tp <0.05 enprostil, 35 #g versus 70 p.g.
ulcer. Furthermore, intragastric and intraduodenal routes of administration were evaluated to contrast the effect of intragastric versus intraduodenal administration. SUBJECTS AND METHODS #
Six subjects with previously documented duodenal ulcer (five men, one woman; mean age, 57 years) were studied. Each subject gave informed written consent to the protocol that was approved by the University of California, San Diego, Human Subjects Committee. They were asymptomatic at the time of the study and were not taking any medications. The diagnosis of duodenal ulcer was previously established by endoscopy or by an upper gastrointestinal series. Experiments were performed after an overnight fast. Each subject participated in seven studies that were separated from one another by about one week. The two doses of enprostil (35/~g or 70/.~g) and placebo were administered ~ither intragastrically or intraduodenally according to a Latin square randomization design, and the study was performed under double-blind conditions. Ranitidine (150 mg) was given intragastrically on the last study day. A radiopaque nasogastric tube (An 10, H.W. Andersen, Oyster Bay, New York) was fluoroscopically positioned so that the tip was in the most dependent portion of the stomach. Basal gastric acid secretion was collected by automatic aspiration (Stedman, ACMI, New York, New York) for 30 minutes and measured by in vitro titration to pH 7 [13]. Enprostil or placebo was delivered intragastrically via the nasogastric tube in a total volume of 10 ml followed by 5 ml of air to empty the delivery line. In the experiments in which enprostil or placebo was given intraduodenally, a small (Fr~ 8) radiopaque tube was positioned so that its tip was 15Jcm beyond the pylorus (at the junction of the third and fourth portion of the duodenum). After enprostil or placebo was infused, phenol red (5 ml, 50 mg per liter) was instilled to ensure that no reflux of drug into the stomach occurred. After 30 minutes, the duodenal tube was removed. Ranitidine was given orally with 10 ml of water. After drug administration, the tube was clamped for 30 minutes. A liquid meal (500 ml, pH 5.5, 40 g protein, 30 g fat, 30 g carbohydrate, 550 Kcal, 768 mOsm) was then instilled into
August 18, 1986
the stomach over three minutes. Gastric acid secretion was measured by automatic intragastric titration to pH 5.5 with 0.5 N sodium hydroxide as the titrant in 30-minute intervals for four hours [14,15]. The stomach was then aspirated completely and a second meal, identical to the first, was instilled. Acid secretion was again measured for four hours. These two meals simulated breakfast and lunch. If either meal emptied before four hours, the time was noted and gastric acid secretion was collected by automatic suction and titrated in vitro to pH 7. Gastric emptying time was approximated as the time after meal instillation when intragastric titration could no longer be carried out. Venous blood samples were obtained at 30-minute intervals throughout the study through an indwelling catheter for the measurement of serum gastrin (kindly performed by Dr. John H. Walsh). The antibody (number 1611) used had an equal affinity for G17 and G34 [16]. Integrated gastrin release was calculated as previously described [7]. Results are shown as means • SEM. The Student t test, analysis of variance, and the Wilcoxon signed-rank test were used in the statistical analysis. Differences were considered statistically significant at a p value of less than 0.05. RESULTS Intragastric Administration, Compared with placebo, both doses of intragastric enprostil and ranitidine significantly suppressed acid secretion over the entire study (Table I). The duration of the acid inhibitory effect by 35 #g of enprostil was approximately six hours, whereas the effect of the 70 #g enprostil dose and ranitidine lasted throughout the eight-hour study (Figure 1). In response to the first meal, both doses of enprostil and the 150 mg dose of ranitidine significantly suppressed four-hour acid output (0.5 to 4.5 hours after dosing). In addition, 70/~g of enprostil and ranitidine significantly suppressed acid secretion in response to the second meal (4.5 to 8.5 hours after dosing). Gastric acid secretion in response to the 35 ~.g dose of enprostil was arithmetically but not statistically less than that in response to placebo after the second meal (Table I). The effect of 70 #g of enprostil was signifi-
The American Journal of Medicine
Volume 81 (suppl 2A)
45
SYMPOSIUM ON GASTROINTESTINAL PROSTAGLANDINS--THOMAS ET AL
ea.s~lDligeaI 1
Meal2
1
11
9
5 "o o (5
Enprosti! 35 ilg
3 2
1 "
Ranitidine 150 mg 31 T24
~ 15 - 36- ~1 7B4 '8 ~1 9A5 ~ 1 ~A..,"T 6 1 97
1I 8 , 1 I T1
,
19
Time (30 min periods)
cantly greater than the effect of the 35 p.g dose during the first 4 hours and during the entire eight-hour test period. There were nosignificant differences between 150 mg of ranitidine and 70 #g of enprostil after the first or second meals or over the entire study (Figure 1). Compared with placebo, the total eight-hour acid output was decreased by 58 -+ 15 percent after 35 #g of enprostil intragastrically, by 8 2 - 11 percent after 70 /~g of enprostil intragastrically, and by 95 - 2 percent after 150 mg of ranitidine intragastrically. Intraduodenal Administration. Intraduodenal administration of both the 35 and 70/~g doses of enprostil significantly suppressed meal-stimulated gastric acid secretion over the eight-hour study (Table I). Meal-stimulated gastric acid secretion was suppressed for approximately fivehours after the 35 #g dose and for seven hours after the 70/~g dose (Figure 2). After the first meal, the 35 and 70 p.g doses of enprostil significantly reduced the four-hour gastric acid secretion. In addition, 70 p.g of enprostil significantly decreased gastric acid secretion after the second meal (Figure 2). The 70/~g dose, when compared with the 35/~g dose, also resulted in a significantly greater reduction of acid secretion after the second meal. Compared with placebo, the total eight-hour gastric acid output was decreased by 6 7 - 9 percent after intraduodenal administration of 35 #g of enprostil and by 91 -+- 3 percent after 70/~g of enprostil. The total eight-hour acid output after intraduodenal administration of 70 /~g of enprostil was similar to that after intragastric administration of 150 mg ranitidine (11.8 - 5.4 mmol per eight-hours and 7.6 4.3 mmol per eight-hours, respectively). Reflux from the duodenum into the stomach (as measured by the presence of phenol red) was not detected in any of the intraduodenal studies. Intragastric versus Intraduodenal Administration. In'tragastrio administration of enprostil produced almost
46
August 18, 1986 The American Journal of Medicine
Figure 1. Mean gastric acid secretion (mmol per 30 minutes) before and after intragastric administration of each drug. Standard errors ranged from 0.1 to 4.5 mmol per 30 minutes. In this figure and subsequent ones, standard errors were omitted for clarity.
identical responses as the same dose given intraduodenally (Table I). Gastric Emptying. No significant difference was demonstrated in emptying times between either meal, drug or route of administration (mean time until emptying equal to 2.5 hours; range, 2.3 to 2.9 hours). Effect on Serum Gastrin and Integrated Gastrin Response. Fasting serum gastrin levels were similar on all
test days, approximately 40 pg/ml. Intragastric administration of 35 and 70/zg of enprostil significantly suppressed the gastrin response to the first meal and muted the response to the second meal (Figure 3). The same doses given intraduodenally produced comparable responses (Figure 4). However, administration of ranitidine did not alter the meal-stimulated serum gastrin response (Figure 3). The integrated gastrin response was calculated as the sum of the change in serum gastrin from basal [7]. This parameter was significantly suppressed by both intragastric doses during the first meal and over the entire eighthour period (Table II). Both intragastric and intraduodenal administration of enprostil suppressed meal-stimulated gastrin release in a dose-related manner. During the entire study, the 35 /~g dose administered intragastrically and intraduodenally decreased the integrated gastrin response by 73 -+ 10 percent and 72 _ 26 percent, respectively; the 70 #g dose administered intragastrically and .intraduodenally reduced this response by 90 - 8 percent and 125 +-- 55 percent, respectively (Table II). COMMENTS
The results of this study indicate that enprostil is a potent inhibitor of both meal-stimulated gastric acid secretion and gastrin release in patients with inactive duodenal ulcer disease. Equal intragastric or intraduodenal doses produced similar reductions in acid secretion and gastrin release. The 70/~g dose of enprostil produced a greater
Volume 81 (suppl 2A)
SYMPOSIUM ON GASTROINTESTINAL P R O S T A G L A N D I N S - - T H O M A S ET AL
Drug
i~
Basal I Meal 1
Meal 2
Placebo
8
7
1 1 Enpmatil
Figure 2. Mean g~stric acid secretion (mmo/ per 30 minutes) before and after intraduodenal administration of each drug. Standard errors ranged from O.1 to 4.2 mmol per 30 minutes.
o 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
Time (30 mln periods)
and more prolonged inhibition when compared with the 35 /zg dose. Moreover, 7 0 / ~ of enprostil caused a similar reduction in gastric acid secretion as 150 mg of ranitidine over the eight-hour test period. Compared with placebo, enprostil did not appear to alter gastric motility. This observation is similar to that of Moore et al [17], who examined liquid and solid emptying after administration of placebo and a synthetic prostaglandin E1 analogue, misoprostol. The mechanisms involved in prostaglandin E-induced ~hibition of gastric acid secretion are most likely multifac-
torial. Soil [18] has reported that natural prostaglandin E2 and prostacyclin inhibited histamine-stimulated aminopyrine accumulation and cyclic adenosine monophosphate production by isolated canine parietal cells. In addition, a number of prostaglandin analogues have a similar effect [19]. Enprostil, but not natural prostaglandin E2, suppressed bombesin-stimulated gastrin release from G cells in vitro (A. Soil, personal communication). It appears that enprostil and possibly some other synthetic E-type prostaglandins suppress acid secretion through at least two distinct mechanisms.
5O
Drug
40
Placebo 9
~
Meal 2
N It (5
_:
u
Figure 3. Change in serum gastrin (pg/ ml) from basal for each 30-minute period after intragastric drug administration. Standard errors ranged from 1.3 to 28.8 pg/ml.
Enprolltil
9
~
~
R
! 11
I 12
"%%*
.
o
-10
-20
I 1
I 2'
I 3
I 4
I 5
I 6
I 7
I 8
I 9
I 10
I I 13 14
I 1 I 15 16 17
I 18
I 19
Time (30 min periods)
August 18, 1986
The American Journal of Medicine
Volume 81 (suppl 2A)
47
SYMPOSIUMONGASTROINTESTINALPROSTAGLANDINS--THOMASETAL
Drug 5O
~, Meal
4O
/
I
Placebo
3O 2O 10
~
0 -10
--20
I ! 1 2
! 3
i
i
i
~ r ~ 4
i
!
i
!
!
1
i
i
i
I
i
I
I
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time ( 3 0 m i n periods)
e A number of studies in humans have shown that synthetic prostaglandins are effective inhibitors of gastric acid production but their effect on gastrin release varies. Enprostil (35 and 70 ,u.g) has previously been shown to significantly suppress meal-stimulated gastric acid secretion and gastrin release in normal males [8]. In addition, Ippoliti and co-workers [3] reported that 16,16-dimethyl prostaglandin E2 inhibited both meal-stimulated gastric acid secretion and gastrin release in patients with duodenal ulcer. Another analogue, 15(R)15-methyl prostaglandin E2, has been observed to suppress gastrin release [4,5,11]. On the other hand, misoprostol [20] and trimoprostil (J. Lenz, personal communication) inhibit gastric acid production without altering serum gastrin. Seventy micrograms of enprostil had a prolonged effect on gastric acid secretion that was similar to the effect of 150 mg of ranitidine. Mahachai et al [9] evaluated 24-hour gastric pH after administration of enprostil on several dos-
T A B L E II
i~g
Enprosti170
age schedules (35 #g at night, 70/zg at night, and 35/~g twice daily) in patients with duodenal ulcer [9]. The 35/zg dose at night significantly elevated nocturnal gastric pH 3.5 to 6 hours after dosing, whereas the other two regimens (70/zg at night and 35/zg twice daily) raised the nocturnal gastric pH 3.5 to 12 hours after administration. The last two responses were similar to those achieved with 600 mg of cimetidine administered twice daily. Interestingly, our results indicate that the route of administration (intragastric or intraduodenal) had no influence on the effect of either the 35 #g or 70 #g dose. Previous studies have demonstrated that 16,16-dimethyl prostaglandin E2, 16,16-dimethyl prostaglandin E2 methyl ester, and 15(S)-15 methyl prostaglandin E2 methyl ester were either ineffective or significantly less effective when administered into the small intestine than when administered intragastrically [3,12]. Our results suggest that enprostil is either better absorbed or undergoes less deg-
Mean (_+SE) Integrated Gastrin R e s p o n s e (ng 9 minute/ml) First Meal (0-4 hours)
Second Meal (4-8 hours)
Total (8 hours)
Intragastric Placebo Enprostil (35/~g) Enprostil (70 #g) Ranitidine (150 rag)
5.6 • 1.8 0.8 • 0.8" -0.9 -'- 0.4* 6.1 • 2.4
7.0 - 2.6 3.3 • 1.3 1.5 -'- 0.4 6.7 • 2.7
12.7 -+ 4.3 4.1 - 2.1" 0.6 • 0.6* 12.8 • 5.0
Intraduodenal Placebo Enprostil (35 p-g) Enprostil (70 #g)
4.4 • ,2.2 0.7 -+-0.7 -1.3 • 0.8"
6.9 • 3.5 2.8 +--1.1 1.1 -'- 1.5
11.4 --+5.7 3.5 -'- 1.4 -0.1 • 2.3"
*p <0.05 compared with placebo.
48
Figure 4. Change in serum gastrin (pg/ ml) from basal for each 30-minute period after intraduodenal administration. Standard errors ranged from 1.5 to 42.3 pg/ ml.
August 18, 1986
The American Journal of Medicine
Volume 81 (suppl 2A)
SYMPOSIUMON GASTROINTESTINALPROSTAGLANDINS--THOMASETAL
radation by the small intestine compared with other prostaglandin analogues. Synthetic series E prostaglandins are a promising group of drugs for the treatment of patients with peptic ulcer disease. Several clinical trials have demonstrated their efficacy in the treatment of duodenal ulcer [21-24]. Our study and those of other investigators [1-12] indicate that part of their beneficial action is likely through the suppression of gastric acid secretion. Furthermore, E class prostaglandins can stimulate a number of "defensive factors." These factors include increased mucus secretion, gastric and duodenal bicarbonate secretion, and mucosal blood flow [25,26]. The precise importance of each of these effects remains to be defined.
in summary, enprostil is a potent inhibitor of mealstimulated gastric acid secretion and gastrin release in patients with inactive duodenal ulcer. The duration of action with the 7 0 / ~ g dose of enprostil persisted for at least eight hours. In contrast to other synthetic prostaglandin E2 analogues, it was equally effective when given either intragastrically or intraduodenally. If enprostil is without untoward effects, it may prove useful in the treatment of patients with peptic ulcer disease. ACKNOWLEDGMENT
We are grateful to Ms. Nancy Hartung for secretarial assistance and to Mr. Jeffrey Sackman and Ms. Mireille AIgazi for technical and statistical help.
REFERENCES
1. Robert A, Schultz R, Nezamis JE, Lancaster C: Gastric antisecretory and antiulcer properties of PGE2, 15-methyl PGE2, and 16,16-dimethyl PGE2. Intravenous, oral and intrajejunal administration. Gastroenterology 1976; 70: 359-370. 2. Hawkey CT, Rampt0n D: Prostagtandinsand the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985; 89:1162-1188. 3. Ippoliti AF, Isenberg JI, Maxwell V, Walsh JH: The effect of 16,16--dimethyl prostaglandin E2 on meal-stimulated gastric acid secretion and serum gastrin in duodenal ulcer patients. Gastroenterology 1976; 70: 488-491. 4. KonturekSJ, Kwiecien N, Swierczek J, Oleksy J, Sito E, Robert A: Comparison of methylated prostaglandin E2 analogues given orally in the inhibition of gastric responsesto pentagastrin and peptone meal in man. Gastroenterology 1976; 70: 683-687. 5. KonturekSJ, Oleksy J, Biernat J, Sito E, Kwiecien N: Effect of synthetic 15-methyl analog of PGE2 on gastric acid and serum gastdn response to peptone meal, pentagastdn, and 9, histamine in duodenal ulcer patients. Dig Dis Sci 1976; 21: 291-295. 6. Konturek SJ, Robed A, Hanchar AJ, Nezamis JE: Comparison of prostacyclin and prostaglandin E2 on gastric secretion, gastrin release, and mucosal blood flow in dogs. Dig Dis Sci 1980; 25: 673-679. 7. Ippoliti AF, Isenberg JI, Hagie L: Effect of oral and intravenous 16,16-dimethyl prostaglandin E2 in duodenal ulcer and ZolI!nger-Ellison syndrome patients. Gastroenterology 1981; 80: 55-59. 8. Davis GR, Walsh JH, Morawski SG, Fordtran JS: Effect of cimetidine and enprostil (a Syntex investigationalprostagiandin E2) on gastric acidity and serum gastdn concentration in normal subjects (abstr). Gastroenterology 1984; 86: 1058. 9. Mahachai V, Walker K, Sevelius H, Thomson ABR: Antisecretory and serum gastrin lowering effect of enprostil in patients with duodenal ulcer disease. Gastroenterologzy1985;89: 555561. 10. Peterson W, Fetdman M, Taylor I, Bremer M: The effect of 15(R)-15-methyi prostaglandin E2 on meal-stimulated gastric acid secretion, serum gastrin, and pancreatic polypeptide in duodenal ulcer patients. Dig Dis Sci 1979; 24: 381-384. 11. Konturek S, Swierczek J, Kwiecien N, Obtolowicz W, Sito E, Olesky J: Effect of orally administered 15(R)-15 methyl PGE2 and/or an anticholingeric drug on meal-induced gastric acid secretion and serum gastrin levels in patients with duodenal ulcers. Scand J Gastroenterol 1979; 14: 813-819. 12. Nylander B, Robert A, Anderson S: Gastric secretory inhibition by certain methyl analogs of prostaglandin E2 following intestinal administration in man. Scand J Gastroenterol 1974; 9:
August 18, 1986
759-762. 13. Gross RA, Isenberg JI, Hogan DL, Samloff IM: Effect of fat on meal-stimulated duodenal acid load, duodenal pepsin load, and serum gastrin in duodenal ulcer and normal subjects. Gastroenterology 1978; 75: 357-362. 14. Hogan DL, Turken D, Stern AI, Isenberg Jh Comparison of the serial dilution indicator and intragastric titration methods for measurement of meal-stimulated gastric acid secretion in man. Dig Dis Sci 1983; 28: 1001-1004. 15. HennRM, Isenberg JI, Maxwell V, Sturdevant RAL: Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 1975; 293: 371-375. 16. Walsh JH: Radioimmunoassay of gastrin. In: Rothfield B, ed. Nuclear medicine in vitro. Philadelphia:J.B. Lippincott Company, 1974; 231-248. 17. Moore J, Alazraki N, Clay G: Effect of synthetic prostaglandinEl analog on gastric emptying of meals in man. Dig Dis Sci 1986; 31: 16-20. 18. Soft AH: Specific inhibition by prostaglandin E2 and 12of hista~ mine-stimulated [14C] aminopyi'ine accumulation and cyclic adenosine monophosphate generation by isolated canine parietal cells. J Cfin Invest 1980; 65: 1222-1229. 19. Soil A, Whittle B: Interaction between prostaglandins and cylic AMP in the gastric mucosa. Prostaglandins1981; 21 (suppl): 39-45. 20. Bauer RF: Misoprostol preclinical pharmacology. Dig Dis Sci 1985:30 (suppl): 118S-'i 25S. 21. BrandDL, Roufail WM, Thomson ABR, Tapper EJ: Misoprostol, a synthetic PGEz analog, in the treatment of duodenal ulcers. Dig Dis Sci 1985; 30 (suppl): 147S-158S. 22. Archambault AP, Halvorsen L, Lee SP, et al: Effic&cy and safety of enprostil, a synthetic prostaglandin,and placebo in patients with duodenal ulcer (abstr). Am J Gastroenterol 1984; 79: 828. 23. VantrappenG, Janssens J, Popiela T, et al: Effect of 15 (R)-15methyl prostaglandin E2 (arbaprostil)on the healing of duodenal ulcer. A double-blind multicenter study. Gastroenterology 1982; 83: 357-363. 24. BrandDL, Roufail WM, Thomson ABR, Tapper EJ: Misoprostol, a prostaglandin E~ analog, is effective in healing duodenal ulcers: results of a multicenter controlled trial (abstr). Gastroenterology 1984; 86: 1034. 25. Flemstrom G, Turnberg L: Gastroduodenal defense mechanisms. In: Isenberg JI, Johansson C, eds. Clinics in gastroenterology, vol. 13, no. 2. London: W.B. Saunders, 1984; 327354. 26. Miller TA: Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol 1983; 245: G601-G623. r
The American Journal of Medicine
Volume 81 (suppl 2A)
49
FRANK J. THOMAS, M.D. MICHAEL A. KO.SS, B.S. DANIEL L. HOGAN, B.A. JON I. ISENBERG, M.D. San Diego, California
Fromthe Divisionof Gastroenterology,Department of Medicine, UCSD Medical Center, Universityof California, San Diego, san Diego, California. This work was supported by a grant from Syntex Research, PaloAlto, California. Requestsfor reprints should be addressed to Dr. Jon I. Isenberg, Division of Gastroenterology, UCSD Medical Center (H-81l-D), 225 Dickinson Street, San Diego, California 92103.
44
The effect of enprostil, a synthetic dehydro-prostaglandin E2, on meal-stimulated gastric acid secretion and gastrin release was studied in six patients with inactive duodenal ulcer disease. Each subject underwent seven tests in random order on separate days: placebo intragastrically and intraduodenally; enprosti135 and 70 pg both intragastrically and intraduodenally; and ranitidine 150 mg intragastrically. After measuring basal gastric acid secretion and gastrin release, a liquid meal (500 ml, pH 5.5, 40 g protein, 30 g fatl 30 g carbohydrate, 550 Kcal, 768 mOsm) was given. Gastric acid secretion and gastrin release were measured over the next four hours. A second identical meal was instilled and both parameters were measured for an additional four hours. Thirty-five and 70 pg of enprostil administered intragastrically reduced total eight-hour gastric acid secretion by 58 percent and 82 percent, respectively (p <0.05). The 35 and 70/~g doses administered intraduodenally decreased gastric acid secretion by 67 percent and 91 percent, respectively (p <0.05 compared with placebo). Ranitidine suppressed gastric acid secretion by 95 percent, which was similar to the suppression achieved with the 70/xg dose of enprostil. The total mealstimulated integrated gastrin response was significantly suppressed by both intragastric doses of enprostil and by the 70 pg dose given intraduodenally (p <0.05). Compared with placebo, the 35 /xg intragastric and intraduodenal doses decreased the integrated gastrin response by 73 percent and 72 percent, respectively. The 70 pg intragastric and intraduodenal doses of enprostil reduced the integrated gastrin response by 90 percent and 125 percent, respectively. Ranitidine did not alter the integrated gastrin response. It is concluded that enprostil significantly inhibited both mealstimulated gastric acid secretion and gastrin release. The response to enprostil occurred in a dose-dependent manner and was similar regardless of the route of administration. Prostaglandins of the E class are potent inhibitors of gastric acid secretion [1-12]. Synthetic analogues of prostaglandin E are more effective than natural prostraglandin E in decreasing acid secretion [1]. Most, but not all, of the synthetic analogues of prostaglandin E2 are more effective inhibitors of gastric acid secretion when administered directly into the stomach rather than into the duodenum [3,12]o Enprostil, a synthetic dehydro-prostaglandin E2, also suppresses gastric acid secretion [8]. This study was undertaken to assess the effect of enprostil on meal-stimulated acid secretion and gastrin release in patients with inactive duodenal
August18, 1986 The American Journal of Medicine Volume81 (suppl 2A)
SYMPOSIUMON GASTROINTESTINALPROSTAGLANDINS--THOMASET AL
TABLE I
Mean (•
Gastric Acid Secretion First Meal (retool/4 hours)
Second Meal (mnlol/4 hours)
Total (mrno[/8 hours)
Intragastric Placebo Enprostil (35/~g) Enprostil (70 #g) Ranitidine (150 mg)
65.2 • 20.1 15.3 -+-5.6* 4.5 • 2.8*t 2.4 • 1.7"
48.6 • 14.2 26.1 --- 10.0 15.0 • 5.2* 5.2 • 3.2*
113.8 - 33.8 43.1 • 14.9~ 19.4 +-- 11.7"t 7.6 --- 4.3*
Intraduodenal Placebo Enprostil (35/~g) Enprostil (70/~g)
60.2 -'- 18.3 13.9 • 6.0" 4.0 • 1.3"
53.4 - 20.2 30.8 • 10.4 7.8 • 4.4 ~
113.6 • 38.0 44.7 -'- 15.7" 11.8 • 5.4*t
*p <0.05 compared with placebo. tp <0.05 enprostil, 35 #g versus 70 p.g.
ulcer. Furthermore, intragastric and intraduodenal routes of administration were evaluated to contrast the effect of intragastric versus intraduodenal administration. SUBJECTS AND METHODS #
Six subjects with previously documented duodenal ulcer (five men, one woman; mean age, 57 years) were studied. Each subject gave informed written consent to the protocol that was approved by the University of California, San Diego, Human Subjects Committee. They were asymptomatic at the time of the study and were not taking any medications. The diagnosis of duodenal ulcer was previously established by endoscopy or by an upper gastrointestinal series. Experiments were performed after an overnight fast. Each subject participated in seven studies that were separated from one another by about one week. The two doses of enprostil (35/~g or 70/.~g) and placebo were administered ~ither intragastrically or intraduodenally according to a Latin square randomization design, and the study was performed under double-blind conditions. Ranitidine (150 mg) was given intragastrically on the last study day. A radiopaque nasogastric tube (An 10, H.W. Andersen, Oyster Bay, New York) was fluoroscopically positioned so that the tip was in the most dependent portion of the stomach. Basal gastric acid secretion was collected by automatic aspiration (Stedman, ACMI, New York, New York) for 30 minutes and measured by in vitro titration to pH 7 [13]. Enprostil or placebo was delivered intragastrically via the nasogastric tube in a total volume of 10 ml followed by 5 ml of air to empty the delivery line. In the experiments in which enprostil or placebo was given intraduodenally, a small (Fr~ 8) radiopaque tube was positioned so that its tip was 15Jcm beyond the pylorus (at the junction of the third and fourth portion of the duodenum). After enprostil or placebo was infused, phenol red (5 ml, 50 mg per liter) was instilled to ensure that no reflux of drug into the stomach occurred. After 30 minutes, the duodenal tube was removed. Ranitidine was given orally with 10 ml of water. After drug administration, the tube was clamped for 30 minutes. A liquid meal (500 ml, pH 5.5, 40 g protein, 30 g fat, 30 g carbohydrate, 550 Kcal, 768 mOsm) was then instilled into
August 18, 1986
the stomach over three minutes. Gastric acid secretion was measured by automatic intragastric titration to pH 5.5 with 0.5 N sodium hydroxide as the titrant in 30-minute intervals for four hours [14,15]. The stomach was then aspirated completely and a second meal, identical to the first, was instilled. Acid secretion was again measured for four hours. These two meals simulated breakfast and lunch. If either meal emptied before four hours, the time was noted and gastric acid secretion was collected by automatic suction and titrated in vitro to pH 7. Gastric emptying time was approximated as the time after meal instillation when intragastric titration could no longer be carried out. Venous blood samples were obtained at 30-minute intervals throughout the study through an indwelling catheter for the measurement of serum gastrin (kindly performed by Dr. John H. Walsh). The antibody (number 1611) used had an equal affinity for G17 and G34 [16]. Integrated gastrin release was calculated as previously described [7]. Results are shown as means • SEM. The Student t test, analysis of variance, and the Wilcoxon signed-rank test were used in the statistical analysis. Differences were considered statistically significant at a p value of less than 0.05. RESULTS Intragastric Administration, Compared with placebo, both doses of intragastric enprostil and ranitidine significantly suppressed acid secretion over the entire study (Table I). The duration of the acid inhibitory effect by 35 #g of enprostil was approximately six hours, whereas the effect of the 70 #g enprostil dose and ranitidine lasted throughout the eight-hour study (Figure 1). In response to the first meal, both doses of enprostil and the 150 mg dose of ranitidine significantly suppressed four-hour acid output (0.5 to 4.5 hours after dosing). In addition, 70/~g of enprostil and ranitidine significantly suppressed acid secretion in response to the second meal (4.5 to 8.5 hours after dosing). Gastric acid secretion in response to the 35 ~.g dose of enprostil was arithmetically but not statistically less than that in response to placebo after the second meal (Table I). The effect of 70 #g of enprostil was signifi-
The American Journal of Medicine
Volume 81 (suppl 2A)
45
SYMPOSIUM ON GASTROINTESTINAL PROSTAGLANDINS--THOMAS ET AL
ea.s~lDligeaI 1
Meal2
1
11
9
5 "o o (5
Enprosti! 35 ilg
3 2
1 "
Ranitidine 150 mg 31 T24
~ 15 - 36- ~1 7B4 '8 ~1 9A5 ~ 1 ~A..,"T 6 1 97
1I 8 , 1 I T1
,
19
Time (30 min periods)
cantly greater than the effect of the 35 p.g dose during the first 4 hours and during the entire eight-hour test period. There were nosignificant differences between 150 mg of ranitidine and 70 #g of enprostil after the first or second meals or over the entire study (Figure 1). Compared with placebo, the total eight-hour acid output was decreased by 58 -+ 15 percent after 35 #g of enprostil intragastrically, by 8 2 - 11 percent after 70 /~g of enprostil intragastrically, and by 95 - 2 percent after 150 mg of ranitidine intragastrically. Intraduodenal Administration. Intraduodenal administration of both the 35 and 70/~g doses of enprostil significantly suppressed meal-stimulated gastric acid secretion over the eight-hour study (Table I). Meal-stimulated gastric acid secretion was suppressed for approximately fivehours after the 35 #g dose and for seven hours after the 70/~g dose (Figure 2). After the first meal, the 35 and 70 p.g doses of enprostil significantly reduced the four-hour gastric acid secretion. In addition, 70 p.g of enprostil significantly decreased gastric acid secretion after the second meal (Figure 2). The 70/~g dose, when compared with the 35/~g dose, also resulted in a significantly greater reduction of acid secretion after the second meal. Compared with placebo, the total eight-hour gastric acid output was decreased by 6 7 - 9 percent after intraduodenal administration of 35 #g of enprostil and by 91 -+- 3 percent after 70/~g of enprostil. The total eight-hour acid output after intraduodenal administration of 70 /~g of enprostil was similar to that after intragastric administration of 150 mg ranitidine (11.8 - 5.4 mmol per eight-hours and 7.6 4.3 mmol per eight-hours, respectively). Reflux from the duodenum into the stomach (as measured by the presence of phenol red) was not detected in any of the intraduodenal studies. Intragastric versus Intraduodenal Administration. In'tragastrio administration of enprostil produced almost
46
August 18, 1986 The American Journal of Medicine
Figure 1. Mean gastric acid secretion (mmol per 30 minutes) before and after intragastric administration of each drug. Standard errors ranged from 0.1 to 4.5 mmol per 30 minutes. In this figure and subsequent ones, standard errors were omitted for clarity.
identical responses as the same dose given intraduodenally (Table I). Gastric Emptying. No significant difference was demonstrated in emptying times between either meal, drug or route of administration (mean time until emptying equal to 2.5 hours; range, 2.3 to 2.9 hours). Effect on Serum Gastrin and Integrated Gastrin Response. Fasting serum gastrin levels were similar on all
test days, approximately 40 pg/ml. Intragastric administration of 35 and 70/zg of enprostil significantly suppressed the gastrin response to the first meal and muted the response to the second meal (Figure 3). The same doses given intraduodenally produced comparable responses (Figure 4). However, administration of ranitidine did not alter the meal-stimulated serum gastrin response (Figure 3). The integrated gastrin response was calculated as the sum of the change in serum gastrin from basal [7]. This parameter was significantly suppressed by both intragastric doses during the first meal and over the entire eighthour period (Table II). Both intragastric and intraduodenal administration of enprostil suppressed meal-stimulated gastrin release in a dose-related manner. During the entire study, the 35 /~g dose administered intragastrically and intraduodenally decreased the integrated gastrin response by 73 -+ 10 percent and 72 _ 26 percent, respectively; the 70 #g dose administered intragastrically and .intraduodenally reduced this response by 90 - 8 percent and 125 +-- 55 percent, respectively (Table II). COMMENTS
The results of this study indicate that enprostil is a potent inhibitor of both meal-stimulated gastric acid secretion and gastrin release in patients with inactive duodenal ulcer disease. Equal intragastric or intraduodenal doses produced similar reductions in acid secretion and gastrin release. The 70/~g dose of enprostil produced a greater
Volume 81 (suppl 2A)
SYMPOSIUM ON GASTROINTESTINAL P R O S T A G L A N D I N S - - T H O M A S ET AL
Drug
i~
Basal I Meal 1
Meal 2
Placebo
8
7
1 1 Enpmatil
Figure 2. Mean g~stric acid secretion (mmo/ per 30 minutes) before and after intraduodenal administration of each drug. Standard errors ranged from O.1 to 4.2 mmol per 30 minutes.
o 1
2
3
4
5
6
7
8
9
10 11 12 13 14 15 16 17 18 19
Time (30 mln periods)
and more prolonged inhibition when compared with the 35 /zg dose. Moreover, 7 0 / ~ of enprostil caused a similar reduction in gastric acid secretion as 150 mg of ranitidine over the eight-hour test period. Compared with placebo, enprostil did not appear to alter gastric motility. This observation is similar to that of Moore et al [17], who examined liquid and solid emptying after administration of placebo and a synthetic prostaglandin E1 analogue, misoprostol. The mechanisms involved in prostaglandin E-induced ~hibition of gastric acid secretion are most likely multifac-
torial. Soil [18] has reported that natural prostaglandin E2 and prostacyclin inhibited histamine-stimulated aminopyrine accumulation and cyclic adenosine monophosphate production by isolated canine parietal cells. In addition, a number of prostaglandin analogues have a similar effect [19]. Enprostil, but not natural prostaglandin E2, suppressed bombesin-stimulated gastrin release from G cells in vitro (A. Soil, personal communication). It appears that enprostil and possibly some other synthetic E-type prostaglandins suppress acid secretion through at least two distinct mechanisms.
5O
Drug
40
Placebo 9
~
Meal 2
N It (5
_:
u
Figure 3. Change in serum gastrin (pg/ ml) from basal for each 30-minute period after intragastric drug administration. Standard errors ranged from 1.3 to 28.8 pg/ml.
Enprolltil
9
~
~
R
! 11
I 12
"%%*
.
o
-10
-20
I 1
I 2'
I 3
I 4
I 5
I 6
I 7
I 8
I 9
I 10
I I 13 14
I 1 I 15 16 17
I 18
I 19
Time (30 min periods)
August 18, 1986
The American Journal of Medicine
Volume 81 (suppl 2A)
47
SYMPOSIUMONGASTROINTESTINALPROSTAGLANDINS--THOMASETAL
Drug 5O
~, Meal
4O
/
I
Placebo
3O 2O 10
~
0 -10
--20
I ! 1 2
! 3
i
i
i
~ r ~ 4
i
!
i
!
!
1
i
i
i
I
i
I
I
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Time ( 3 0 m i n periods)
e A number of studies in humans have shown that synthetic prostaglandins are effective inhibitors of gastric acid production but their effect on gastrin release varies. Enprostil (35 and 70 ,u.g) has previously been shown to significantly suppress meal-stimulated gastric acid secretion and gastrin release in normal males [8]. In addition, Ippoliti and co-workers [3] reported that 16,16-dimethyl prostaglandin E2 inhibited both meal-stimulated gastric acid secretion and gastrin release in patients with duodenal ulcer. Another analogue, 15(R)15-methyl prostaglandin E2, has been observed to suppress gastrin release [4,5,11]. On the other hand, misoprostol [20] and trimoprostil (J. Lenz, personal communication) inhibit gastric acid production without altering serum gastrin. Seventy micrograms of enprostil had a prolonged effect on gastric acid secretion that was similar to the effect of 150 mg of ranitidine. Mahachai et al [9] evaluated 24-hour gastric pH after administration of enprostil on several dos-
T A B L E II
i~g
Enprosti170
age schedules (35 #g at night, 70/zg at night, and 35/~g twice daily) in patients with duodenal ulcer [9]. The 35/zg dose at night significantly elevated nocturnal gastric pH 3.5 to 6 hours after dosing, whereas the other two regimens (70/zg at night and 35/zg twice daily) raised the nocturnal gastric pH 3.5 to 12 hours after administration. The last two responses were similar to those achieved with 600 mg of cimetidine administered twice daily. Interestingly, our results indicate that the route of administration (intragastric or intraduodenal) had no influence on the effect of either the 35 #g or 70 #g dose. Previous studies have demonstrated that 16,16-dimethyl prostaglandin E2, 16,16-dimethyl prostaglandin E2 methyl ester, and 15(S)-15 methyl prostaglandin E2 methyl ester were either ineffective or significantly less effective when administered into the small intestine than when administered intragastrically [3,12]. Our results suggest that enprostil is either better absorbed or undergoes less deg-
Mean (_+SE) Integrated Gastrin R e s p o n s e (ng 9 minute/ml) First Meal (0-4 hours)
Second Meal (4-8 hours)
Total (8 hours)
Intragastric Placebo Enprostil (35/~g) Enprostil (70 #g) Ranitidine (150 rag)
5.6 • 1.8 0.8 • 0.8" -0.9 -'- 0.4* 6.1 • 2.4
7.0 - 2.6 3.3 • 1.3 1.5 -'- 0.4 6.7 • 2.7
12.7 -+ 4.3 4.1 - 2.1" 0.6 • 0.6* 12.8 • 5.0
Intraduodenal Placebo Enprostil (35 p-g) Enprostil (70 #g)
4.4 • ,2.2 0.7 -+-0.7 -1.3 • 0.8"
6.9 • 3.5 2.8 +--1.1 1.1 -'- 1.5
11.4 --+5.7 3.5 -'- 1.4 -0.1 • 2.3"
*p <0.05 compared with placebo.
48
Figure 4. Change in serum gastrin (pg/ ml) from basal for each 30-minute period after intraduodenal administration. Standard errors ranged from 1.5 to 42.3 pg/ ml.
August 18, 1986
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Volume 81 (suppl 2A)
SYMPOSIUMON GASTROINTESTINALPROSTAGLANDINS--THOMASETAL
radation by the small intestine compared with other prostaglandin analogues. Synthetic series E prostaglandins are a promising group of drugs for the treatment of patients with peptic ulcer disease. Several clinical trials have demonstrated their efficacy in the treatment of duodenal ulcer [21-24]. Our study and those of other investigators [1-12] indicate that part of their beneficial action is likely through the suppression of gastric acid secretion. Furthermore, E class prostaglandins can stimulate a number of "defensive factors." These factors include increased mucus secretion, gastric and duodenal bicarbonate secretion, and mucosal blood flow [25,26]. The precise importance of each of these effects remains to be defined.
in summary, enprostil is a potent inhibitor of mealstimulated gastric acid secretion and gastrin release in patients with inactive duodenal ulcer. The duration of action with the 7 0 / ~ g dose of enprostil persisted for at least eight hours. In contrast to other synthetic prostaglandin E2 analogues, it was equally effective when given either intragastrically or intraduodenally. If enprostil is without untoward effects, it may prove useful in the treatment of patients with peptic ulcer disease. ACKNOWLEDGMENT
We are grateful to Ms. Nancy Hartung for secretarial assistance and to Mr. Jeffrey Sackman and Ms. Mireille AIgazi for technical and statistical help.
REFERENCES
1. Robert A, Schultz R, Nezamis JE, Lancaster C: Gastric antisecretory and antiulcer properties of PGE2, 15-methyl PGE2, and 16,16-dimethyl PGE2. Intravenous, oral and intrajejunal administration. Gastroenterology 1976; 70: 359-370. 2. Hawkey CT, Rampt0n D: Prostagtandinsand the gastrointestinal mucosa: are they important in its function, disease, or treatment? Gastroenterology 1985; 89:1162-1188. 3. Ippoliti AF, Isenberg JI, Maxwell V, Walsh JH: The effect of 16,16--dimethyl prostaglandin E2 on meal-stimulated gastric acid secretion and serum gastrin in duodenal ulcer patients. Gastroenterology 1976; 70: 488-491. 4. KonturekSJ, Kwiecien N, Swierczek J, Oleksy J, Sito E, Robert A: Comparison of methylated prostaglandin E2 analogues given orally in the inhibition of gastric responsesto pentagastrin and peptone meal in man. Gastroenterology 1976; 70: 683-687. 5. KonturekSJ, Oleksy J, Biernat J, Sito E, Kwiecien N: Effect of synthetic 15-methyl analog of PGE2 on gastric acid and serum gastdn response to peptone meal, pentagastdn, and 9, histamine in duodenal ulcer patients. Dig Dis Sci 1976; 21: 291-295. 6. Konturek SJ, Robed A, Hanchar AJ, Nezamis JE: Comparison of prostacyclin and prostaglandin E2 on gastric secretion, gastrin release, and mucosal blood flow in dogs. Dig Dis Sci 1980; 25: 673-679. 7. Ippoliti AF, Isenberg JI, Hagie L: Effect of oral and intravenous 16,16-dimethyl prostaglandin E2 in duodenal ulcer and ZolI!nger-Ellison syndrome patients. Gastroenterology 1981; 80: 55-59. 8. Davis GR, Walsh JH, Morawski SG, Fordtran JS: Effect of cimetidine and enprostil (a Syntex investigationalprostagiandin E2) on gastric acidity and serum gastdn concentration in normal subjects (abstr). Gastroenterology 1984; 86: 1058. 9. Mahachai V, Walker K, Sevelius H, Thomson ABR: Antisecretory and serum gastrin lowering effect of enprostil in patients with duodenal ulcer disease. Gastroenterologzy1985;89: 555561. 10. Peterson W, Fetdman M, Taylor I, Bremer M: The effect of 15(R)-15-methyi prostaglandin E2 on meal-stimulated gastric acid secretion, serum gastrin, and pancreatic polypeptide in duodenal ulcer patients. Dig Dis Sci 1979; 24: 381-384. 11. Konturek S, Swierczek J, Kwiecien N, Obtolowicz W, Sito E, Olesky J: Effect of orally administered 15(R)-15 methyl PGE2 and/or an anticholingeric drug on meal-induced gastric acid secretion and serum gastrin levels in patients with duodenal ulcers. Scand J Gastroenterol 1979; 14: 813-819. 12. Nylander B, Robert A, Anderson S: Gastric secretory inhibition by certain methyl analogs of prostaglandin E2 following intestinal administration in man. Scand J Gastroenterol 1974; 9:
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759-762. 13. Gross RA, Isenberg JI, Hogan DL, Samloff IM: Effect of fat on meal-stimulated duodenal acid load, duodenal pepsin load, and serum gastrin in duodenal ulcer and normal subjects. Gastroenterology 1978; 75: 357-362. 14. Hogan DL, Turken D, Stern AI, Isenberg Jh Comparison of the serial dilution indicator and intragastric titration methods for measurement of meal-stimulated gastric acid secretion in man. Dig Dis Sci 1983; 28: 1001-1004. 15. HennRM, Isenberg JI, Maxwell V, Sturdevant RAL: Inhibition of gastric acid secretion by cimetidine in patients with duodenal ulcer. N Engl J Med 1975; 293: 371-375. 16. Walsh JH: Radioimmunoassay of gastrin. In: Rothfield B, ed. Nuclear medicine in vitro. Philadelphia:J.B. Lippincott Company, 1974; 231-248. 17. Moore J, Alazraki N, Clay G: Effect of synthetic prostaglandinEl analog on gastric emptying of meals in man. Dig Dis Sci 1986; 31: 16-20. 18. Soft AH: Specific inhibition by prostaglandin E2 and 12of hista~ mine-stimulated [14C] aminopyi'ine accumulation and cyclic adenosine monophosphate generation by isolated canine parietal cells. J Cfin Invest 1980; 65: 1222-1229. 19. Soil A, Whittle B: Interaction between prostaglandins and cylic AMP in the gastric mucosa. Prostaglandins1981; 21 (suppl): 39-45. 20. Bauer RF: Misoprostol preclinical pharmacology. Dig Dis Sci 1985:30 (suppl): 118S-'i 25S. 21. BrandDL, Roufail WM, Thomson ABR, Tapper EJ: Misoprostol, a synthetic PGEz analog, in the treatment of duodenal ulcers. Dig Dis Sci 1985; 30 (suppl): 147S-158S. 22. Archambault AP, Halvorsen L, Lee SP, et al: Effic&cy and safety of enprostil, a synthetic prostaglandin,and placebo in patients with duodenal ulcer (abstr). Am J Gastroenterol 1984; 79: 828. 23. VantrappenG, Janssens J, Popiela T, et al: Effect of 15 (R)-15methyl prostaglandin E2 (arbaprostil)on the healing of duodenal ulcer. A double-blind multicenter study. Gastroenterology 1982; 83: 357-363. 24. BrandDL, Roufail WM, Thomson ABR, Tapper EJ: Misoprostol, a prostaglandin E~ analog, is effective in healing duodenal ulcers: results of a multicenter controlled trial (abstr). Gastroenterology 1984; 86: 1034. 25. Flemstrom G, Turnberg L: Gastroduodenal defense mechanisms. In: Isenberg JI, Johansson C, eds. Clinics in gastroenterology, vol. 13, no. 2. London: W.B. Saunders, 1984; 327354. 26. Miller TA: Protective effects of prostaglandins against gastric mucosal damage: current knowledge and proposed mechanisms. Am J Physiol 1983; 245: G601-G623. r
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