Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement), pp. 126S-129S Effects of Misoprostol on Gastric Acid and Mucus Secretion in Man DONALD E. WILSON, MD, ELIZABETH QUADROS, PhD, TRIKANTE RAJAPAKSA, MD, ANDREA ADAMS, and MARK NOAR, MD Misoprostol, a synthetic prostaglandin E1 analog, at doses of 200, 400, or 800 Ixg, and placebo were administered orally in random fashion to eight healthy male volunteers. The effects on basal and pentagastrin (0.6 p~g/kg/hr) -stimulated acid and mucus (N-acetyl- neuraminic acid measurement) secretion were then determined. Misoprostol in 200-, 400-, and 800-~xg doses reduced basal acid secretion by 91%, 93%, and 93%, respectively. Mean 2-hr acid secretion was reduced by 27%, 33% (P < 0.01), and 51% (P < 0.01), respectively. Reductions in secretory volumes paralleled acid changes. Mucus secretion increased by 37%, 82%, and 95% during the basal period following misoprostol doses of 200, 400, and 800 p~g, respectively. Increase in mucus of 27%, 31%, and 38% was observed during maximal acid inhibition (1-30 min) by misoprostol in 200-, 400-, and 800-~g doses. The concentration of gastric juice mucus was significantly increased. Subjects experienced no significant side effects during the study, and there were no significant changes in hematological or chemical blood studies. Misoprostol, a potent inhibitor of gastric acid secretion, also stimulates mucus secretion. This mucogenic effect may be important in the mucosal protective action of misoprostol and its antiulcer efficacy in man. Misoprostol, (-)-methyl-(11,13E)- ll,16-dihydroxy- 16-methyl-9-oxoprost- 13-en- 1-oate, a synthetic pros- taglandin E1 analog, is a potent antisecretory agent in animals (1, 2). Several reports have also indicated that it has mucosal protective effects in animals and, more recently, in man (3-5). Misoprostol has been shown to be effective therapy for ulcer disease in man (6). Prostaglandins may accelerate ulcer healing due to their acid antisecretory actions. However, the mucosal protective effects, or cytoprotection, of these compounds can be separated from their ef- fects on acid secretion in animal studies and, there- fore, may also play a role in ulcer healing (7). From the Department of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York. This study was supported in part by a grant (RR-318) from the General Clinical Research Centers Program of the Division of Research Resources, National Institutes of Health. Address correspondence to: Dr. Donald E. Wilson, Professor and Chairman, Department of Medicine, SUNY-Downstate Medi- cal Center, 450 Clarkson Avenue, Brooklyn, New York 11203. Although the mechanism of prostaglandin-induced mucosal protection is not precisely known, prosta- glandins affect a number of parameters, including the gastric mucosal barrier, gastric mucosal blood flow, bicarbonate and mucus secretion, and cell proliferation and migration (8-16). Prostaglandins have previously been shown to stimulate gastric mu- cus secretion in animals and man and to increase mucus synthesis in the rat gastric mucosa (10-12). It is possible that this mucogenic effect may play a role in the mucosal protective actions of prostaglandins. In the present study, we have compared the effects of single 200-, 400-, and 800-txg doses of misoprostol with placebo on basal gastric acid and mucus secretion and on gastric acid and mucus secretion following pentagastrin stimulation. MATERIALS AND METHODS Eight healthy men, aged 22-33 years, were given placebo and each of three doses of misoprostol (200, 400, 126S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 0163-2116/86/0200-126S$05.00/0 (cid:14)9 1986 Plenum Publishing Corporation
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`EFFECTS ON GASTRIC ACID AND MUCUS SECRETION TABLE 1. EFFECTS OF MISOPROSTOL ON BASAL AND PENTAGASTRIN- STIMULATED GASTRIC MUCUS SECRETION* Secretion (~g) Misoprostol (~g) Time (min) Placebo 200 400 800 -15 to 0 (Basal) 1464 (cid:127) 300 2004(cid:127) 546 2670 (cid:127) 2860 (cid:127) 795 1-30 2686 ~ 542 3382 (cid:127) 444 3522 (cid:127) 782 3709 (cid:127) 405 31-60 2487 (cid:127) 438 2020 (cid:127) 313 2530 (cid:127) 522 2187 (cid:127) 319 61-90 2317 (cid:127) 268 2506 (cid:127) 523 2913 (cid:127) 754 2471 (cid:127) 429 91-120 2584 (cid:127) 369 2223 (cid:127) 263 2425 (cid:127) 439 2608 (cid:127) 482 *Results are mean - 1 SEM (N = 8). Measured as total N-acetylneuraminic acid (NANA). and 800 Ixg) at weekly intervals, in a randomized, double- blind crossover study. Following an overnight fast, the subjects swallowed either placebo or drug, supplied as four identical white tablets, with 150 ml of water. For- ty-five minutes later, a nasogastric tube (18F) was placed in the dependent portion of the stomach, and stomach contents were evacuated. A basal specimen of gastric juice was then collected for 15 min, after which gastric secretion was stimulated by the intravenous infusion of pentagastrin in normal saline at a dose of 0.6 ~g/kg/hr. For the next 2 hr (divided into eight 15-min collection periods), gastric contents were collected by continuous aspiration and stored on ice. Throughout the procedure, subjects were questioned and observed closely for possi- ble side effects. Immediately before and after the exper- imental time periods, subjects underwent complete phys- ical examinations and a series of laboratory tests, includ- ing urinalysis, CBC, and a standard blood chemistry panel (glucose, BUN, Na +, CI-, K +, CO2, Ca ++, creat- inine, uric acid, SGOT, SGPT, alkaline phosphatase, bilirubin, LDH, GGT, cholesterol, and triglycerides). A history was also taken. Following the test period, each 15-min specimen was analyzed as follows. The volume of the sample was measured, and a 1-ml aliquot was titrated to pH 7.0 with 0.1 N NaOH in an automatic titrator (TTT 81 Digital Titrator, Radiometer, Copenhagen), in order to determine gastric acid content. The remainder of the gastric juice was homogenized by hand and an aliquot assayed for mucus content by determining the amount of glycoprotein-bound N-acetylneumminl'c acid (NANA), using the thiobarbituric acid method of Warren (17) as modified by Roboz et al (18). NANA is the major sialic acid identified in human mucus glycoprotein. These determinations may not precisely re- fleet changes in the gtycoprotein molecule (19). Statistical Analysis. The data from the 15-min, penta- gastrin-stimulated collections were pooled into half-hour collection periods for statistical analysis of NANA, gas- tric acid, and volumes. A paired t test was employed with P < 0.05 denoting statistical significance. RESULTS During the basal period, misoprostol in doses of 200, 400, and 800 ~g increased mucus (NANA) secretion by 37%, 82%, and 95%, respectively (Ta- ble 1). A stimulatory effect on mucus output could also be seen with pentagastrin-stimulated secretion. During the first 30 min of pentagastrin stimulation following misoprostol doses of 200,400, and 800 ~g, mucus secretion was increased by 26%, 31%, and 38%, respectively (Table 1). Mucus concentration was significantly increased by misoprostol during TABLE 2. EFFECTS OF MISOPROSTOL ON BASAL AND PENTAGASTRIN- STIMULATED GASTRIC MUCUS CONCENTRATION (NANA)* Time (min) Placebo 200 Concentration (~g/ml) Misoprostol (Ixg) 400 800 Basal 37.5 - 3.8 55.7 - 6.7? 72.6 --- 10.8t 87.6 --- 21.1 1-30 26.8 (cid:127) 5.6 62.6 (cid:127) 26.2 48.4 - 4.9 49.6 --- 2.6~ 31--60 20.5 --- 3.2 25.8 (cid:127) 4.2 30.7 --- 4.3 29.7 (cid:127) 3.7 61-90 21.6 + 2.5 23.3 --- 3.0 27.3 (cid:127) 3.3 32.4 --- 3.8:~ 91-120 24.0 - 2.9 24.9 (cid:127) 1.7 24.6 - 2.9 30.1 - 3.3:~ *Results are mean __ 1 SEM. "~P < 0.05. :~P < 0.01. Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 127S
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`WILSON ET AL 14 12 1C Acid Output (mEq) 8 0 P M M M P M M M P M M M P M M M 200 Mg 400/~g 800 Fg 200 k4g 400 Fg 800/~g 2O0/4g 400 Mg 800/ag 200 Mg 400 big 800 ~g "p< .05 I"p< .01 1-30 31-60 61-90 91-120 Sp< .001 Time (rain) Fig 1. Effect of misoprostol in doses of 200, 400, and 800 p~g on pentagastrin-stimutated gastric acid output during four consecutive 30-rain intervals. Mean -+ 1 SEN. the basal period. The misoprostol 800-~g dose also significantly increased mucus concentration during pentagastrin stimulation (Table 2). Basal acid secretion decreased from 1.67 - 0.90 meq to 0.15 -+ 0.08, 0.11 --- 0.11, and 0.12 +-- 0.10 meq following misoprostol doses of 200, 400, and 800 Ixg, respectively. The 800-1xg dose of misopros- tol significantly inhibited pentagastrin-stimulated acid secretion during the entire 2-hr period, while the 400-~g dose significantly reduced acid secretion for 1 hr (Figure 1). Maximal inhibition occurred during the first 30-rain period and was 45%, 60%, and 65% for misoprostol doses of 200, 400, and 800 Ixg, respectively. Mean 2-hr gastric secretion was significantly reduced by misoproStol at all three doses (Table 3). Subjects experienced no significant side effects during the study, and there were no significant changes in hematological or chemical blood studies or urinalyses. DISCUSSION The antisecretory effects of misoprostol on basal and stimulated gastric acid secretion in man were confirmed in the present study. In addition, miso- prostol increased both the total output and concen- tration of mucus in gastric juice. In general, a dose--response was observed, with misoprostol 800 ~g causing a doubling of mucus output during the basal period. However, these changes were not statistically significant (P < 0.10). Similarly, the increases in total mucus output observed during pentagastrin stimulation were not significant. How- ever, significant increases in NANA concentrations were observed during the basal and stimulation periods. Prostaglandin-induced mucosal protection, termed cytoprotection, is multifactorial. While the gastric mucosal barrier does not appear to be of major importance in explaining cytoprotection, vascular TABLE 3. EFFECTS OF MISOPROSTOL ON PENTAGASTRIN-STIMULATED GASTRIC SECRETION* Misoprostol (p,g) Placebo 200 400 800 Acid (meq) 41.56 --+- 6.58 30.47 --- 3.72 28.10 -+ 5.75t 20.36 --- 3.22t Volume (ml) 453 -+ 32 357 --- 255 355 -+ 40~ 313 --- 33t *Results are mean -+ 1 SEM. tP < 0.01. SP < 0.05. 128S Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement)
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`EFFECTS ON GASTRIC ACID AND MUCUS SECRETION permeability and change in mucosal blood flow together with maintenance of the mucus gel layer appear to be viable mechanisms. Prostaglandin stimulation of glycoprotein and bicarbonate secre- tion into the mucus gel layer has been well docu- mented (20, 21). It is likely that no currently pro- posed single prostaglandin-induced event can fully define cytoprotection, but that multiple simulta- neous events with differing degrees of importance (depending upon the insulting agent) combine to effect the prostaglandin action. Mucogenesis has previously been suggested as the major mechanism by which carbenoxolone exerts its antiulcer effect. Recent studies indicate that carbenoxolone may increase mucosal prostaglandin levels by reducing the metabolism of prostaglandins (22). The mucogenic effects of misoprostol may be important to the efficacy of this compound in treat- ing and preventing mucosal injury. REFERENCES 1. Dajani EZ, Driskill DR, Bianchi RG, Collins PW, Pappo R: SC-29333, a potent inhibitor of canine gastric secretion. Dig Dis Sci 21:1049-1057, 1976 2. Colton DG, Driskill DR, Phillips EL, Poy P, Dajani EZ: Effect of SC-29333, an inhibitor of gastric secretion, on canine gastric mucosal blood flow and serum gastrin levels. Arch Int Pharmacodyn Ther 236:86-95, 1978 3. Larsen KR, Jensen NF, Davis EK, Jensen JC, Moody FG: The cytoprotective effects of (-+)-15-deoxy-16-alpha, beta- hydroxy-16-methyl PGEI, methyl ester (SC-29333) versus aspirin on shock gastric ulcerogenesis in the dog. Prostaglan- dins 21(Suppl):l19-124, 1981 4. Hunt JN, Smith JL, Jiang CL, Kessler L: Effect of synthetic prostaglandin E~ analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci 28(10):897-902, 1983 5. Cohen MM, Clark L, Armstrong L, D'Souza J: Reduced aspirin-induced fecal blood loss with simultaneous adminis- tration of misoprostol (PGE methyl analogue). Gastroenter- ology 84:1127, 1983 (abstract) 6. Agrawal NM, Saffouri B, Kruss DM, Callison DA, Dajani EZ: Healing of benign gastric ulcer: A placebo-controlled comparison of two dosage regimens of misoprostol, a syn- thetic analog of prostaglandin E~. Dig Dis Sci 30(Sup- pl): 164S-170S, 1985 7. Robert A: Prostaglandins and the concept of cytoprotection. Ann Intern Med 95:616-618, 1981 8. Dajani EZ, Callison DA, Bertermann RE: Effects of E- prostaglandins on canine gastric potential difference. Dig Dis Sci 23:436-442, 1978 9. Wilson DE, Levine RA: The effect of prostaglandin E1 on canine gastric acid secretion and gastric mucosal blood flow. Am J Dig Dis 17:527-532, 1972 10. Garner A, Heylings JR: Stimulation of alkaline secretion in amphibian-isolated gastric mucosa by 16,16-dimethyl PGE2 and PGF2~. Gastroenterology 76:497-503, 1979 11. Kaymakcalan H, Ramsamooj E, Wilson DE: The effect of novel prostaglandin (PG)E1 analogue (CL 115,574) on gastric acid and mucus secretion in man. Prostaglandins 28:5-12, 1984 12. Tao P, Wilson DE: Effects of prostaglandin E2, 16,16- dimethyl prostaglandin E2 and a prostaglandin endoperoxide analogue (U-46619) on gastric secretory volume H§ and mucus synthesis and secretion in the rat. Prostaglandins 28:353-366, 1984 13. Szaho S, Trier JS, Brown A, Schnoor J: Early vascular injury and increased vascular permeability in gastric muco- sal injury caused by ethanol in the rat. Gastroenterology 88:228-236, 1985 14. Leung FW, Itoh M, Hirabayashi K, Guth PH: Role of blood flow in gastric and duodenal mucosal injury in the rat. Gastroenterology 88:281-289, 1985 15. Isenberg JI, Smedfors B, Johansson C: Effect of graded doses of intraluminal H § prostaglandin E2 and inhibition of endogenous prostaglandin synthesis on proximal duodenal bicarbonate secretion in unanesthetized rat. Gastroenterol- ogy 88:303-307, 1985 16. Tarnawski A, Hollander D, Stachura J, Krause WJ, Gergely H: Prostaglandin protection of the gastric mucosa against alcohol injury--a dynamic time-related process. Role of the mucosal proliferative zone. Gastroenterology 88:334-352, 1985 17. Warren L: Thiobarbituric acid assay of sialic acids. Methods in Enzymol 6:463-465, 1963 18. Roboz J, Suttajit M, Bekesi JA: Elimination of 2-deoxyri- bose interference in the thiobarbituric acid determination of N-acetylneuraminic acid in tumor cells by pH-dependent extraction with cyclohexanone. Anal Biochem 110:380-388, 1981 19. Sellers LA, Carroll NJH, Allen A: Misoprostol-induced increases in adherent gastric mucus thickness and luminal mucus output. Dig Dis Sci 31(Suppl):91S-95S, 1986 20. McQueen S, Allen A, Garner A: Measurement of gastric and duodenal mucus gel thickness. In Mechanisms of Mucosal Protection in the Upper Gastrointestinal Tract. A Allen, G Flemstrom, A Garner, W Silen, LA Turnberg (eds). New York, Raven Press, 1984, pp 215-221 21. Kivilaakso E, Flemstrom G: Surface pH gradient and prostaglandin cytoprotection in gastroduodenal mucosa. In Mechanisms of Mucosal Protection in the Upper Gastroin- testinal Tract. A Allen, G Flemstrom, A Garner, W Silen, LA Turnberg (eds). New York, Raven Press, 1984, pp 227-232 22. Rask-Madsen J, Bukhave K, Madsen PER, Bekker C: Effect of carbenoxolone on gastric prostaglandin E2 levels in pa- tients with peptic ulcer disease following vagal and penta- gastrin stimulation. Eur J Clin Invest 13:351-356, 1983 Digestive Diseases and Sciences, Vol. 31, No. 2 (February 1986 Supplement) 129S
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