0002-9270/82/7712-0902
`AMERICAN JOURNAL OF GASTROENTEROLOGY
`Copyright© 1982 by The Am. Coll. of Gastroenterology
`
`Vol. 77. No. 12.1982
`Printed in U.S.A.
`
`Inhibition of Nocturnal Gastric Secretion in Normal Human
`Volunteers by Misoprostol: A Synthetic Prostaglandin E 1
`Methyl Ester Analog
`
`K. Akdamar, M.D., N. Agrawal, M.D., and A. Ertan, M.D.
`Tulane University School of Medicine, Section of Gastroenterology, New Orleans, Louisiana
`
`Misoprostol (SC-29333) is a synthetic prostaglandin
`E 1 analog that has been found to be a potent inhibitor of
`gastric secretion in animals. Nocturnal gastric antisecre(cid:173)
`tory activity of misoprostol, in tablet form, was studied
`in 16 adult volunteers, under basal condition. The study
`was a randomized, double-blind, cross-over, comparison
`of placebo, and three graded doses of misoprostol (50,
`100, and 200 p.g). Misoprostol exhibited a statistically
`significant inhibition of total acid output only at the 200
`p.g dose and this inhibition was maintained for 3 h
`postadministration of the drug. The antisecretory effects
`of misoprostol were characterized by suppression of H+
`ion but not of the volume of gastric secretion. No unto(cid:173)
`ward effects were noted in the volunteers. As a conse(cid:173)
`quence of the gastric antisecretory effects, the present
`studies indicate that misoprostol is a promising therapeu(cid:173)
`tic agent for the treatment of peptic ulcer.
`
`INTRODUCTION
`
`Prostaglandins are a family of saturated, oxygenated
`fatty acids found in most organs and probably formed in
`every mammalian cell. Approximately 20 natural pros(cid:173)
`taglandins have been identified and synthesized. Several
`naturally occurring prostaglandins, such as PGEJ, PGE2,
`and PGAI, inhibit gastric secretion both in animals (1-
`3) and humans_~6).
`Unfortunately, the naturally occurring prostaglandins
`are very susceptible to metabolic degradation which
`would thus limit their therapeutic usefulness. Attempts
`to increase the bioavailability and duration of action of
`. prostaglandins have been made in general,
`through
`methylation of carbon-15 (C-15) or carbon-16 (C-16) of
`natural prostaglandins. In addition, the transposition of
`the C-15 hydroxyl group to the adjacent C-16 position
`significantly improved the gastric antisecretory action of
`PGE, (7). The increased potency is a result of enhanced
`stability against the enzyme 15 hydroxy prostaglandin
`dehydrogenase.
`Misoprostol is a novel synthetic prostaglandin E, an(cid:173)
`alog. The chemical name is (±) methyl II, 16-dihydroxy(cid:173)
`16-methyl-9-oxoprost-13E-en-I-oate (Fig I). Preclinical
`pharmacological studies in animals have shown that
`misoprostol possesses potent and long-lasting gastric an-
`
`902
`
`tisecretory activity. In gastric fistula and Heidenhain
`pouch dogs, misoprostol blocks histamine, pentagastrin,
`and meal-stimulated gastric secretions (8). Furthermore,
`this drug inhibits the development of acute upper gas(cid:173)
`trointestinal ulcerations in animals (9, 10).
`The purpose of this study was to determine whether
`SC-29333 shows nocturnal gastric antisecretory activity
`in normal male subjects under a basal, unstimulated
`condition as measured by total acid output.
`
`MATERIALS AND METHODS
`
`Sixteen healthy male adult volunteers were random(cid:173)
`ized into a double-blind cross-over comparison of pla(cid:173)
`cebo and misoprostol in 50, 100, and 200 p.g doses. Their
`age range was 19-38 yr, with a mean age of 25.6 yr.
`Subjects had no history of psychiatric disorder, drug, or
`alcohol abuse. Concomitant medication, particularly as(cid:173)
`pirin-containing
`or
`nonsteroidal
`antiinflammatory
`agents were prohibited. Each subject was maintained on
`his usual diet throughout the total study period of 4 wk
`and was instructed not to drink alcoholic beverages for
`at least 24 h before each study session. Subjects were not
`permitted to smoke during testing.
`The study protocol was submitted to the institutional
`human research committee for its review and ultimate
`approval. Written informed patient consent was obtained
`from each subject before he was entered into the study.
`Within 7 days before entrance into the study each
`individual had a medical history and physical examina(cid:173)
`tion as well as base-line laboratory studies which in(cid:173)
`cluded complete blood count, urinalysis, and serum
`chemistry proftle (SMAC20). Subjects were admitted to
`the study unit the afternoon of the day that a nocturnal
`gastric secretory study was to be done. A standard meal
`was given at 5:00 PM. This meal consisted of 90 g
`(uncooked weight) co"arsely ground tenderloin steak,
`cooked and seasoned with 1 g salt, 25 g white bread, 8 g
`butter, 60 g vanilla ice cream topped with 35 g chocolate
`-G
`syrup, and 240 ml water (9). At 9:00 PM a no. 14
`tube was positioned in the most dependent part of the
`stomach under fluoroscopic control. At 10:00 PM test
`tablets plus 150 ml tap water were given. At 11:00 PM
`gastric contents were aspirated, volume, pH, and H+
`
`Page 1 Dr. Reddy's Exh. 1059
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`

`

`December 1982
`o
`
`(t,
`
`MISOPROSTOL AND GASTRIC SECRETION
`
`903
`
`,~COOCH3
`
`14
`
`o'''''------,----~---~----_---
`PLACEBO
`~ Ne [)('lSE
`100 MCG DOSE
`200. 001[
`
`DOSE
`
`FIG. 2. Dose differences in acid output for the first 2 h of gastric
`aspiration (h 2 and 3 postdose). Uncertainty intervals are calcutated
`using Tukey's method of honest significant difference.
`
`~
`
`)
`
`I'
`
`I
`
`1
`
`1
`
`I
`
`I
`
`I
`
`110
`
`100
`
`'40
`
`120
`
`'00
`
`10
`
`10
`
`40
`
`!...
`
`~
`:::J
`...J
`0
`>
`
`...J...~
`
`0~ z.
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`..
`...
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`~
`
`0 ........- - - . . , . . . . . - - -........- - - - , - - - - . . . . . , . . . . - - - -
`!!O.,eG 00S(.
`IOOMCG DOSE
`200MC; DOSE
`~ACEIO
`
`DOSE
`
`FIG. 3. Dose differences in volume for the first 2 h of gastric
`aspiration (h 2 and 3 postdose). Uncertainty intervals are calculated
`using Tukey's method of honest significant differ.ence.
`
`after receiving the last test dose, laboratory studies were
`repeated. During the course of the study and in 1 wk
`follow-up evaluation, none of the individuals who par(cid:173)
`ticipated in the study showed any significant adverse
`reaction.
`
`DISCUSSION
`
`Preclinical pharmacological studies in animal models
`have demonstrated that misoprostol possesses potent and
`long-lasting gastric antisecretory activity (8). This inhi(cid:173)
`bition is characterized by suppression of volume, acid
`concentration, and pepsin secretion. In the study, we
`showed that
`the only significant suppression of acid
`output occurred in the first 2 h (h 2 and 3 postdose) and
`only with the 200 J.1.g dose. Contrary to the suppression
`
`~ OH
`
`I. Chemical structure of misoprostol (SC-29333).
`
`HO
`FIG.
`
`were measured. After this initial collection, gastric con(cid:173)
`tents were continuously aspirated and collected in eight
`consecutive I-h samples for which total acid and total
`volume of gastric juice were measured. The determina(cid:173)
`tion of pH was done using a standard glass electrode
`(Beckman Model no. 3500). Hydrogen ion concentration
`was measured by titration method with 0.1 N NaOH to
`pH 7.
`In order to increase the precision of the estimates for
`duration of treatment effects, the 8-h measurements were
`combined into four consecutive 2-h measurements. Sep(cid:173)
`arate analyses of variance were t_hen performed for acid
`and volume of gastric fluid secreted. Based on the results
`of these analyses, 95% Tukey confidence intervals were
`calculated using an approximate mean square error ob(cid:173)
`tained by pooling the heterogeneous variances (12, 13).
`These Tukey confidence intervals were used for making
`multiple comparisons of treatment means for each 2-h
`collection period.
`
`RESULTS
`
`Results of statistical analyses illustrate the effect of
`misoprostol on total acid output and volume over each
`2-h collection period. Dose response effect of the drug
`on total acid output over the first 2-h collection period,
`h 2 and 3 postdose, is shown in Figure 2. The plot is
`constructed so that any two means are significantly
`different at the 5% level if their Tukey confidence inter(cid:173)
`vals do not overlap. The interval for placebo has been
`extended horizontally as a rectangle for each comparison
`with the three active doses. This analysis shows that
`during the first 2-h collection period, the only significant
`difference in mean acid output was between placebo and
`the 200 J.1.g dose of misoprostol (Fig. 2). A similar com(cid:173)
`parison for the second 2-h collection period, h 4 and 5
`postdose, showed no statistically significant differences
`among the treatment means. When samples from the
`third and fourth 2-h collection periods were analyzed,
`again no statistically significant differences were ob(cid:173)
`served.
`The same analysis was applied to the volume of gastric
`fluid secreted and the results are shown in Figure 3. The
`four treatments did not differ significantly in mean fluid
`volume secreted during the first 2-h collection period,
`nor did they differ in subsequent collections. One week
`
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`904
`
`AKDAMAR et al.
`
`this suppression was not
`noted in the animal studies,
`long lasting. Furthermore, there was no significant re(cid:173)
`duction in gastric fluid secreted. We did not measure
`pepsin output in this study.
`Mild and transient nausea, headaches, dizziness, and
`abdominal discomfort were occasionally observed in the
`initial misoprostol clinical studies. In the present study
`none of the participants expressed any significant com(cid:173)
`plaints. Although prostaglandins have the capacity to
`produce hypotension, this was not encountered in this
`group ofvolunteers. Isolated elevations ofSGOT, SGPT,
`or bilirubin were reported in the initial tolerance and
`antisecretory studies. In our experiment, pre- and posts(cid:173)
`tudy liver function tests failed to show these changes.
`Misoprostol prevents the development of ulcerations
`in several acute ulcer models (9, 10). The basis for the
`antiulcer actions of misoprostol may be the inhibition of
`gastric acid as shown in this study or reduction of pepsin
`secretion. In addition, misoprostol possesses cytoprotec(cid:173)
`tive property since it inhibits the development of exper(cid:173)
`imental ulcer,
`in the rat, at doses that do not inhibit
`gastric acid secretion (10). Similar findings are also
`reported for PGE2 (12). Misoprostol has also been dem(cid:173)
`onstrated to strengthen the integrity of gastric mucosal
`barrier against aspirin-induced back diffusion of hydro(cid:173)
`gen ion (15, 16).
`As a consequence of the gastric antisecretory effects
`noted in the present study and the cytoprotective effects
`observed in animals, misoprostol is a promising thera(cid:173)
`peutic agent for the treatment of peptic ulcer disease.
`Clinical multicenter trials with misoprostol in patients
`with gastric or duodenal ulcers are now being done.
`
`CONCLUSIONS
`
`1) Misoprostol exhibits a statistically significant effect
`on nocturnal gastric total acid output as compared to
`placebo only at the highest dose used (200 Jlg).
`2) This significant effect was observed only during
`the first 3 h after misoprostol administration.
`3) Misoprostol had no effect on the volume of noc(cid:173)
`turnal gastric fluid secreted.
`
`ACKNOWLEDGMENTS
`
`The authors wish to thank Mr. William J. Chiappetta
`
`Vol. 77, No. 12, 1982
`
`for technical assistance and Dr. Esam Z. Dajani for
`editorial assistance.
`
`Reprint requests: Kemal Akdamar, M.D., F.A.C.G., Professor of
`Medicine, Chief, Section of Gastroenterology, 1430 Tulane Avenue,
`New Orleans, LA 70112.
`
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