Br. J. clin. Pharmac. (1985), 19, 9-12
`
`Inhibition of food stimulated acid secretion by misoprostol, an
`orally active synthetic E1 analogue prostaglandin
`
`J. K. RAMAGE, A. DENTON & J. G. WILLIAMS
`Royal Naval Hospital, Plymouth, UK
`
`1 The effect of 200 ,ug misoprostol (a synthetic prostaglandin E1 analogue) on food
`stimulated intragastric acidity has been monitored over a 9 h period in 16 normal
`volunteers.
`Misoprostol caused a significant inhibition of intragastric acidity for 2 h post-dosing,
`2
`but no significant effect was seen thereafter on either basal or food stimulated acidity.
`
`Keywords
`
`misoprostol
`
`gastric acid secretion
`
`prostaglandin E1 analogue
`
`Introduction
`
`Misoprostol (SC-29333, Figure 1) is a synthetic
`prostaglandin El analogue that has been shown
`to be a potent inhibitor of gastric acid secretion
`in animals (Dajani et al., 1976). It has also been
`established in animals that doses which do not
`significantly inhibit acid output may have an
`ulcer protective effect (Colton et al., 1979,
`Larsen et al., 1981). In man misoprostol has
`been shown to reduce nocturnal histamine
`(Akdamar et al., 1982) and food stimulated
`secretion (Dajani & Polk, 1981) in doses up to
`200 ,ug given orally. The duration of action of
`the drug has not been established and we have
`therefore investigated the effect of misoprostol
`200 ,ug on repeated food stimulated acid
`secretion in normal volunteers, over a 9 h
`period.
`
`Methods
`
`Food stimulated gastric acid secretion was
`measured by monitoring the intragastric acidity
`0
`0
`
`CH3
`
`OCH3
`
`HO
`
`OH
`Chemital formula of misoprostol.
`Figure 1
`Correspondence: Surgeon Commander J. G. Williams,
`Haslar, Gosport, Hampshire P012 2AA, UK.
`
`9
`
`in response to an homogenous liquid meal
`instilled down a nasogastric tube. This meal
`consisted of one 375 ml can of Clinifeed 500
`(Roussel Ltd) to which a single oxo cube was
`added. This was warmed to 37°C and diluted to
`550 ml with water. The composition of the meal
`was protein 42 g, carbohydrate 79 g, fat 12 g
`and osmolality 510 mmol/l. The pH of the meal
`was adjusted to 5.5 with a few drops of
`concentrated HCI (AnalaR) immediately before
`instillation into the stomach.
`The subjects were normal fit male volunteers
`with no past history of significant gastro-
`intestinal or other disease. No concurrent
`medication was allowed and no subjects were
`permitted to smoke or drink ethanol, coffee or
`tea during the study days or the preceding 24 h.
`The volunteers attended on 2 separate study
`days at least 1 week apart. After an overnight
`fast a 14 FR gauge nasogastric tube (Salem,
`Sump, Sherwood Medical Industries Inc) was
`passed and positioned under X-ray control to
`the most dependent part of the stomach. At
`09.00 h the test tablets were administered by
`mouth with 200 ml of water. At 09.30 h the test
`meal was instilled down the nasogastric tube.
`For the next 90 min mixing was continuous by
`repeated aspiration and reinstillation of the
`gastric contents through a 50 ml syringe and
`by turning the subjects from the resting left
`decubitus position over to the right and back
`Professor of Naval Medicine, Royal Naval Hospital,
`
`Page 1 Dr. Reddy's Exh. 1058
`
`

`

`J. K. Ramage, A. Denton & J. G. Williams
`10
`the study uneventfully except one who vomited
`again every 10 min. Every 5 min a 5 ml
`during his final meal. He has been excluded
`sample of gastric contents was aspirated and the
`from analysis of the data for the third meal. At
`pH measured to the nearest 0.01 pH unit using
`the end of the first meal (2 h post dose) the pH
`a combined glass electrode and digital pH
`of the gastric contents was markedly less with
`meter (pHM72,
`Copenhagen,
`Radiometer
`placebo (3.42 + 0.19 s.e. mean) than with
`Denmark). After measurement the samples
`misoprostol (4.38 + 0.18 s.e. mean). Mean pH
`were returned to the stomach. The electrode
`for the duration of this meal was 4.97 following
`was kept to 37°C in buffers of pH 4 and pH 7
`misoprostol and 4.51 following placebo (P <
`and its calibration was checked before each
`0.001). At the end of the second meal the
`reading.
`difference was smaller and at the end of the
`At 90 min the stomach was emptied. pH
`third meal there was very little difference
`measurements were made at 30 min intervals
`between the two treatments (3.30 for miso-
`until 13.00 h when the test meal procedure was
`prostol, 3.34 for placebo). For the second and
`repeated exactly as before. At 14.30 h the
`third meals, mean pH on misoprostol was not
`stomach was again emptied and pH measure-
`significantly different from placebo; second
`ments made at 30 min intervals until 17.00 h
`meal 4.43 ± 0.11 vs 4.33 ± 0.11, third meal
`when the test meal was again repeated. This
`4.38 ± 0.12 vs 4.39 ± 0.11, respectively.
`sequence of events is summarised in Figure 2.
`The mean pH during both interdigestive
`The subjects were studied on two occasions
`periods was higher for misoprostol than placebo
`at least 1 week apart, receiving either miso-
`(between first and second meal misoprostol
`prostol 200 ,ug or identical placebo according
`2.48 ± 0.36, placebo 1.94 ± 0.12, between
`to a predetermined random order. The studies
`second and third meal misoprostol 2.45 + 0.38,
`were conducted double-blind.
`placebo 2.05 ± 0.11 but the difference was not
`Before and 24 h after each study blood and
`statistically significant for either period. These
`urine were taken for assessment of routine
`results have been displayed graphically
`in
`haematology and biochemistry.
`Figure 3.
`For comparison of the effects of misprostol vs
`No subject complained of any untoward
`placebo the pH response to the meal was
`effects during or after the studies apart from
`compared by three way analysis of variance
`one volunteer who vomited 30 min after the
`with subject, treatment and treatment period as
`start of his third meal. This is thought to be due
`factors. The data were analysed as pH, and not
`to irritation from his nasogastric tube and he
`converted to mmol/l H+ since pH is more
`rapidly recovered once this was withdrawn. No
`normally distributed and is hence more suitable
`subject complained of diarrhoea.
`for analysis of variance (Lucas, 1977).
`No significant abnormal results were seen on
`haematological or biochemical screening.
`
`Results
`
`Sixteen normal subjects (all male, mean age 28
`years, s.e. mean 1.13, range 20-35, mean
`weight 73.5 kg, s.e. mean 3.4, range 54-107)
`were studied. All sixteen subjects completed
`
`Discussion
`
`These results indicate that misoprostol inhibits
`food stimulated gastric acidity significantly for
`
`Tablets
`
`NG
`tube
`
`Meal 1
`
`Stomach
`emptied
`
`I
`08.00
`
`I
`
`I
`09.00
`
`I
`
`I
`10.00
`
`I
`
`I I
`
`I
`11.00
`
`I
`
`I
`
`I
`I
`12.00
`
`Meal 2I
`
`13.00
`
`Stomach
`emptied
`
`Meal 3
`
`ach
`Stoma
`ied
`empti
`
`I
`I
`14.00
`
`I
`I Il
`I
`15.00
`16.00
`17.00
`
`18.00 Time (h)
`
`30 min
`5 min
`5 min
`samples
`samples
`samples
`Figure 2 Summary of sequence of events during each study.
`
`30 min
`samples
`
`5 min
`samples
`
`Page 2 Dr. Reddy's Exh. 1058
`
`

`

`Misoprostol, a prostaglandin E, analogue
`
`11
`
`4
`
`3
`
`2
`
`13.o
`
`14.0
`
`15.00
`
`16.00
`
`17.00
`
`'18.0
`
`4
`
`13
`
`2
`
`10.00
`
`11.00
`
`12.00
`
`1.<~~~~~~~~~~~~~(
`
`Figure 3 Mean pH (± s.e. mean) plotted against time for 16 subjects receiving misoprostol 200 ,ug
`(0) or placebo (x).
`
`up to 2 h post-dosing. Acidity in response to the
`second meal (4 h post dose) also shows some
`inhibition though without statistical significance.
`The inhibition of basal gastric acidity seen when
`measured from 2 h post-dosing is not statistically
`significant.
`The method used is simple, well tolerated
`and is comparable with previous 24 h studies
`which have measured intragastric acidity by
`aspiration of samples (Pounder et al., 1975,
`1976).
`It gives no information concerning
`volume of secretion and it does not quantify
`actual acid output but assesses acidity while the
`stomach responds to the meal in a physiological
`manner. The meal used is a potent stimulus to
`acid secretion causing a mean acid output of
`greater than 40 mmol/h when measured by in
`vivo titration (Williams et al., 1983).
`
`The mean rise in pH during breakfast (to
`4.38) in the misoprostol group is greater than
`that
`in the control group (to
`3.42). This
`difference is less than that seen with cimetidine
`400 mg, using an identical technique (unpub-
`lished data). In the light of evidence of cytopro-
`tection in animal studies (Colton et al., 1979;
`Larsen et al., 1981) it will be of interest to see
`whether misoprostol, given orally in a single
`dose of relatively low potency and short duration
`of action as an antisecretory agent will be
`effective in the healing of peptic ulcers.
`
`We are grateful to the Medical Officer-in-Charge,
`Royal Naval Hospital Plymouth, for permission to
`perform these studies and to G. D. Searle & Co, High
`Wycombe, Buckinghamshire, for supplies of miso-
`prostol. We are also grateful to Mrs Jeanette Rawlins
`for clerical assistance.
`
`References
`
`Akdamar, K., Agrawal, N. & Ertan, A. (1982).
`Inhibition of nocturnal gastric secretion in normal
`human volunteers by misoprostol: a synthetic
`prostaglandin El methyl ester analog. Am J.
`Gastroenterol., 77, 902-904.
`Colton, D. G., Callison, D. A. & Dajani, E. Z.
`(1979). Effects of prostaglandin El derivative, SC-
`29333, and aspirin on gastric ionic fluxes and
`potential difference in dogs. J. Pharmac. exp.
`Ther., 210, 283-288.
`
`Dajani, E. Z., Driskill, D. R., Bianchi, R. G.,
`Collins, P. W. & Pappo, R. (1976). SC-29333: A
`inhibitor
`gastric
`secretion.
`of canine
`potent
`Digestive Diseases, 21, 1049-1057.
`Dajani, E. Z. & Polk, R. C. (1981). G. D. Searle &
`Co. Investigational Brochure for SC-29333, a
`gastric antisecretory agent.
`Larsen, K. R., Jensen, N. F., Davis, E. K., Jensen,
`J. C. & Moody, F. G. (1981). The cytoprotective
`(+)-15-deoxy-16-a,
`effects
`of
`,-hydroxy-16-
`
`Page 3 Dr. Reddy's Exh. 1058
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`

`

`12
`
`J. K. Ramage, A. Denton & J. G. Williams
`methyl PGE1, methyl ester (SC-29333) versus
`intragastric acidity by cimetidine in duodenal
`aspirin-shock gastric ulcerogenesis in the dog.
`ulcer patients. Lancet, ii, 1069-1072.
`Prostaglandins, 21, Suppl., 119-24.
`Williams, J. G., Robertson, R. J. & Milton-Thompson,
`Lucas, M. (1977). pH or hydrogen ion concentrations
`G. J. (1983). Inhibition of food stimulated acid
`in statistics. Lancet, Ui, 826.
`secretion by fenoctimine, a new anti-secretory
`Pounder, R. E., Williams, J. G., Milton-Thompson,
`agent. Br. J. clin. Pharmac., 15, 673-676.
`(1976).
`G. J. & Misiewicz, J.
`Effect of
`J.
`cimetidine on 24 h intragastric acidity in normal
`subjects. Gut, 17, 133-138.
`Pounder, R. E., Williams, J. G., Milton-Thompson,
`G. J. & Misiewicz, J. J. (1975). 24 h control of
`
`(Received January 31, 1984,
`accepted September 2, 1984)
`
`Page 4 Dr. Reddy's Exh. 1058
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