Scandinavian Journal of Gastroenterology
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Effects of Nocloprost on Gastric Functions in Man S. J. Konturek, N. Kwiecien, W. Obtulowicz, J. Maczka, Z. Hebzda & J. Oleksy To cite this article: S. J. Konturek, N. Kwiecien, W. Obtulowicz, J. Maczka, Z. Hebzda & J. Oleksy (1991) Effects of Nocloprost on Gastric Functions in Man, Scandinavian Journal of Gastroenterology, 26:11, 1145-1151, DOI: 10.3109/00365529108998606 To link to this article: http://dx.doi.org/10.3109/00365529108998606
Published online: 08 Jul 2009.
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Effects of Nocloprost on Gastric Functions in Man S. J . KONTUREK, N. KWIECIEN, W. OBTULOWICZ, J. MACZKA, 2. HEBZDA & J. OLEKSY Institute of Physiology, Academy of Medicine, Cracow, Poland
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Konturek SJ, Kwiecien N, Obtulowicz W, Maczka J , Hebzda Z , Oleksy J . Effects of nocloprost on gastric functions in man. Scand J Gastroenterol 1991,26, 1145-1151 Previous studies in animals and humans demonstrated that nocloprost, a stable prostaglandin E2analogue, shows very high gastroprotective potency, relatively weak gastric inhibitory activity, and low systemic bioavailability after oral administration. In this study the effects of nocloprost on gastric acid secretion and intraluminal pH and on gastric emptying and plasma gastrin levels were determined in humans. Nocloprost at doses of 50 and 100 pg was ineffective, but at a dose of 200 pg it reduced the response to pentagastrin significantly and that to a peptone meal by 30-S0% and abolished plasma gastrin response without affecting the rate of gastric emptying, Nocloprost given at a dose of 100 pg three times daily 30 min before the major meals (breakfast, lunch, and dinner) did not affect intragastric pH significantly as monitored by continuous intraluminal pH-metry. We conclude that nocloprost does not affect gastric acid secretion or intraluminal pH when applied at a dose (SO-100 pg) that is gastroprotective and that is proposed for peptic ulcer therapy. A higher dose (200 pg) of nocloprost causes moderate gastric acid inhibition and suppression of plasma gastrin release without affecting gastric emptying or causing any side effects. Key words: Gastric emptying; gastrin; prostaglandin; stomach
Prof. Dr. S. 1. Konturek, Institute of Physiology, 31-531 Krakow, ul. Grregorzecka 16. Poland
The therapeutic success of potent antisecretory drugs such as H2-receptor antagonists (H2RA) or omeprazole (1,2) supports the notion that acidpeptic activity plays a crucial role in the pathogenesis of peptic ulceration (3,4) and that the inhibition of this activity provides a favourable environment for ulcer healing ( 5 ) . Stable methylated analogues of prostaglandin El (PGE1) or PGE2 are potent direct inhibitors of gastric acid secretion (6) at a site close to the adenylate cyclase in parietal cells (7,s).By decreasing the acid output or intraluminal acid concentration these analogues can promote healing of gastroduodenal ulcerations (9) and minimize the mucosal damage by agents such as aspirin (10,ll). When viewed solely in terms of ability to suppress acid secretion, PGs do not offer any significant therapeutic advantages over H2RA (9). Several stable analogues have so far been proposed in the therapy of gastric mucosal disorders,
but actually only misoprostol and enprostil have been used clinically. The major drawback of PGs is that they are not superior to H2RA in peptic ulcer therapy, and they may cause some side effects such as diarrhoea and uterine contractions, excluding their use in pregnant women or during the child-bearing age. Thus, despite the welldocumented cytoprotective activity (12), the dinical use of PGs in gastric disorders is a t present rather limited (9-11). Attempts have been made to obtain PG derivatives that are without gastric antisecretory activity but retain gastroprotective and ulcer-healing effects without any potential hazards. Nocloprost is a PGE2 analogue that both in experimental animals (13,14) and in humans seems to fulfil the requirements of a clinically useful PG because of very low systemic bioavailability, relatively weak gastric antisecretory action, and predominantly local protective and ulcer-healing properties (15).
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This study was designed to explore in humans the effects of nocloprost on exocrine and endocrine gastric secretion and motility after oral administration at the dose range that was shown to be highly protective against aspirin damage in humans (15).
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MATERIALS AND METHODS Subjects Studies were carried out on 28 duodenal ulcer patients divided into 3 groups (A, B, and C), the mean age being 22 years (range, 19-23 years) and mean weight 74 kg (range, 68-77 kg). All subjects were in clinical remission, confirmed by endoscopy, when the study period began. Each patient gave informed consent, and the study was approved by Institutional Ethical Committee. All subjects were hospitalized, and 1week before the study all medication was withdrawn and alcohol was forbidden. Study design Three series of secretory tests were performed, each on a separate group of 8-10 subjects. Group A subjects were used for the secretory studies with pentagastrin infusion, group B subjects for studies with a peptone meal, and group C for studies with 24-h pH-metry. In tests with pentagastrin (2 pg/kg-h) infusion, gastric juice was collected after an overnight fast, by means of a standard aspiration technique using a double-lumen tube as described previously (6). The acidity of the juice was measured by titrating 0.2-ml samples with 100mM NaOH, using an automatic titrator (Autoburet, Radiometer, Copenhagen, Denmark). Acid outputs were expressed in millimoles per 15 min. Pepsin concentration was determined with a modification of the Anson haemoglobin method (6) and expressed as milligrams pepsin per milliliter by reading the trichloracetic acid supernatant spectrophotometrically at 280 nm and comparing the results with those of solutions incubated with different pepsin standards (hog pepsin, Pentex Biochemical, Kankakee, Ill., USA). Pepsin outputs were calculated taking into consideration the dilution of samples and expressed as milligrams pepsin per 15 min.
RANITIDINE 150 mgld a;i----+L--+--4, 1
CONTROL
1
W~AL
i
i
3
i
1Smin PERIODS Fig. 1 . Effects of nocloprost at doses of 50, 100, or 200 pg and ranitidine at dose of 150 mg on pentagastrinstimulated gastric acid and pepsin outputs. Means ? SEM of eight tests in eight subjects. Asterisks indicate significant ( P < 0.05) decrease below the control value.
Nocloprost, 9~-chloro-16,16-dimethyl PGE2, was supplied in tablets of 50 or 100 pg by Asche AG, Hamburg, Germany, as prostag1andin-Bcyclodextrin complex as clathrate to ensure better stability and water solubility of the compound. Placebo tablets of similar appearance were also provided by Asche AG. Each subject was studied five times separated by 4- to 5-day periods, receiving nocloprost at 50, 100, or 200 pg per dose during one period, 150 mg ranitidine (Glaxo, Ware, U.K.) or placebo during the other periods, with sequence randomized in a double-blind manner. In group B a double-lumen tube was introduced into the stomach of overnight-fasted subjects, and after complete gastric emptying, basal gastric acid secretion was obtained by suction-aspiration for 30 min. Two tablets of nocloprost (200 pg) or
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Nocloprost and Gastric Function
placebo were then given, the gastric aspiration was stopped for 30min, and then a liquid meal consisting of 8% peptone (Bactopeptone, Difco Lab., Detroit, Mich., USA) adjusted to pH 5.5 (with 1 M NaOH) was introduced into the stomach in a volume of 300 ml during each of four consecutive 30-min periods. The stomach was emptied completely before the administration of the next 300-ml meal. Phenol red (15 mg) was added to each meal, and its concentration was determined spectrophotometrically at pH 11, at a wavelength of 540 nm. Gastric content was continuously mixed by the aspiration-perfusion system, and the meal-stimulated acid secretion was measured by intragastric titration with end point of pH 5.5, using 50 mM NaOH as described previously (6). The gastric residual at the end of each 30min meal was measured with the phenol red dye dilution technique (16). Gastric emptying was expressed in percentage as the difference between the original amount of dye marker added to the meal at time 0 and its fraction remaining in the stomach at the end of each 30-min period (17). In group C subjects 24-h intragastric pH was continuously monitored with monocrystal antimony pH probe (Synectics, Sweden) connected to a portable microprocessor recording unit (Digitrapper, Synectics, Sweden) (18,19). The outer diameter of the electrode was 2.1 mm, and it was inserted through a nostril and positioned in the lower corpus region of the stomach (controlled fluoroscopically at the beginning of each test). The electrode was fixed on the cheek with a small piece of adhesive tape. The distance between the electrode tip and the nostril was kept constant in a given subject. The Digitrapper unit was easily carried around in a small bag. The investigation started at 1200 h and continued until 1200 h the next day. The menus for breakfast (B), lunch (L), and light dinner (D) were similar on each day. Each subject underwent two studies during which 24-h intragastric acidity was monitored, and nocloprost (100 Fg) or a placebo tablet was ingested about 30 min before each meal. Twenty-four hours of the measurement periods were analysed by means of a computer program (Gastrogram version 5.44, Gastrosoft Inc.,
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Sweden). From the data obtained, the summary report of 24-h intragastric pH recording and the cumulative percentage of the frequency distribution of various pHs could be determined in tests with placebo and nocloprost. For statistical evaluation the whole 24-h record was divided into periods with pH of 1-2, 2-3, 3-4, 4-5, 6-7, and 7-8 in tests with nocloprost or placebo. Assessments Blood samples were taken from the peripheral vein into tubes containing 2500 U aprotinin (Trasylol@,Bayer, Germany) and 0.5 mg of ethylenediaminetetraacetic acid (EDTA) before and at 30-min intervals in tests with peptone meal or before and 30 min after major meals in 24-h pHrecording tests. Plasma gastrin and pancreatic polypeptide (PP) were measured by specific radioimmunoassays as described previously (621). The assay systems were sufficiently sensitive to detect 1.5pM gastrin and 2.5 pM PP.
NOCLOPROST (2OOyg3 PEPTONE MEAL 1501
- 1 -E .- 15-
CONTROL 0
E E
----W'NOCLOPROST
S
1
2
3 k 30min PERIODS
S
Fig. 2. Effects of nocloprost (200 pg) on plasma gastrin and gastric acid responses to a 8% peptone meal. Means 2 SEM of 10 tests in 10 subjects. Asterisks indicate significant (P < 0.05) decrease below the control value.
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In all tests routine records of arterial blood pressure, pulse rate, and body temperature were made 30 min after the administration of nocloprost or placebo. All subjects were questioned concerning untoward gastrointestinal and other side effects and asked to report any alterations in bowel movements during the 24 h after the last treatment dose of nocloprost. Results are expressed as means k SEM. Analysis of variance or the Duncan multiple range test was used to evaluate significance between the experimental procedures. Differences with P < 0.05 were considered significant.
RESULTS Acid and pepsin outputs in response to intravenous infusion of pentagastrin alone and penta-
gastrin with nocloprost given orally at doses of 50, 100, or 200 yg are shown in Fig. 1. Nocloprost at 50 and 1OOyg was ineffective. At a dose of 200 pg nocloprost reduced acid outputs significantly, by about 30-40%. Ranitidine at 150 mg completely abolished the acid response to pentagastrin in these subjects. Pepsin outputs were also increased in response to pentagastrin infusion, but pretreatment with nocloprost at any dose used did not affect pepsin secretion. In contrast, ranitidine almost completely abolished the pepsin response to pentagastrin. lntragastric administration of 8% peptone meal caused about threefold increase in acid secretion over basal values (Fig. 2). Acid outputs were well sustained during the consecutive 30-min periods, reaching in the second 30-min meal about 12 mmol/30 min or about 75% of pentagastrin-
Fig. 3. Typical summary intragastric p H graph versus time, showing one-channel pH recording in the same subject treated with placebo or nocloprost (100 pg/dose) three times daily. Arrows indicate the ingestion of major meals, breakfast (B), lunch (L), and dinner (D), and the time of administration of placebo or nocloprost tablets before each meal. The inset above shows the summary pH and frequency distribution in the tests.
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Nocloprost and Gastric Function
induced maximal acid output (16.20 +- 3.28 mmol/30 min) in these subjects. Nocloprost administered in a dose of 200 pg before the meal reduced the acid response to peptone by about 35-50%. Gastric emptying of a peptone meal in control tests with placebo averaged about 64% of the marker (phenol red) added to the meal. In tests with nocloprost on average 55% of the marker added to the peptone meal was emptied into the duodenum. The difference in the emptying rate between tests with placebo and nocloprost was not significant. Plasma gastrin concentration was elevated twoto three-fold after the peptone meal, and the pretreatment with nocloprost significantly reduced this postprandial gastrin elevation (Fig. 2). Plasma PP increased from a basal value of about 15.5 5.3 pM to 65.2 12.4 pM after the meal, and this increment was also significantly reduced (to about 36.7 8.8 pM) by the pretreatment with nocloprost. The 24-h intragastric pH curves recorded in the same subject treated with placebo or nocloprost is shown in Fig. 3. Both with placebo and with nocloprost medication the normal circadian course of pH curves with typical rise after meals and low values during the nighttime were recorded. The frequency distribution of total 24-h recording of pH readings was similar in placebo
*
*
*
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Table I. Plasma gastrin concentrations after major meals in placebo-treated and nocloprost-treated subjects Plasma gastrin (pM) Placebo
Breakfast Lunch Dinner
Nocloprost
Before
After
Before
After
3724 41 5 3527
5624* 79* 8* 97211*
3925 34 7 3728
44*5’F 53 *8t 61 2 1 2 * t
*
*
* Significant (P < 0.05) increase above the value recorded before the meal. t Significant (P < 0.05) decrease below the corresponding value recorded in placebo-treated subjects.
and nocloprost treatment. The comparison of the values at all pH levels showed no statistically significant difference between placebo and nocloprost treatment (Fig. 4). Plasma gastrin concentrations showed typical increments after each major meal in placebo-treated subjects. In tests with nocloprost administration before each meal, the increments in plasma gastrin were significantly smaller (Table I). No symptoms or side effects were recorded at any dose of nocloprost used. In no instance was there any significant change in blood pressure, pulse rate, body temperature, or bowel movements.
0 PLACEBO NOCLOPROST
PH
Fig. 4.Cumulative percentage distribution of total pH recording in subjects receiving placebo or nocloprost (100 pg) tablets three times daily 30 min before each major meal. Means ? SEM of 10 tests in 10 subjects.
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DISCUSSION This study demonstrates that nocloprost, a novel PGE2 analogue, does not affect gastric acid and pepsin secretion at the doses (50-100 pg) that were found to protect the human stomach against aspirin damage (15) and that are used in peptic ulcer therapy. At the higher dose (2001.18) nocloprost resulted in the moderate inhibition of gastric acid secretion and in the suppression of gastrin release without affecting gastric emptying or causing any side effects. Previous studies in animals (13, 14) demonstrated that nocloprost given intragastrically is highly effective against various types of mucosal lesions, including ethanol, aspirin, taurocholate, or stress. The protective doses applied intragastrically failed to alter gastric acid secretion but increased gastric alkaline secretion and mucosal blood flow, suggesting that nocloprost is capable of activating local protective mechanisms without alterating acid secretion. Since duodenal administration of nocloprost was ineffective, and a labelled compound (3H-nocloprost) introduced into the gut appeared only in a small fraction in the peripheral blood, it was accepted that this PG analogue undergoes extensive degradation in the mucosa and the liver, resulting in a very low (about 2%) systemic bioavailability. These experimental studies indicate that nocloprost has a unique ability to act locally on the gastric mucosa and reaches the systemic circulation in the active form only in small amounts. This explains the high degree of dissociation between the protective effects and the systemic actions on other organs, so that nocloprost is virtually devoid of systemic PGE2-like side effects. Indeed, no side effects were observed in our subjects treated with nocloprost up to the dose of 200 pg. No changes in the blood pressure, pulse rate, or body temperature and no gastrointestinal symptoms such as diarrhoea were recorded in the subjects tested with nocloprost. It is of interest that the plasma gastrin and PP, which increased two- to three-fold after the peptone meal, were significantly suppressed by the pretreatment with nocloprost (Fig. 2). As the dose of nocloprost (200pg) used was shown in tests with pentagastrin to inhibit gastric acid se-
cretion, it was expected to cause a compensatory increase in basal or peptone-stimulated plasma gastrin due to the interruption of normal feedback suppression of the G-cells by low intragastric pH. The fact that nocloprost suppressed the plasma gastrin response to a meal could not be explained by its effect on gastric acid secretion and suggests that the inhibition of the postprandial gastric acid secretion by this PG is mediated, at least in part, by direct action on the gastrin-secreting G-cells. Thus nocloprost, unlike histamine H antagonists or omeprazole (22,23), does not potentiate but rather suppresses food-stimulated gastrin levels. This could prevent any rebound hypersecretion that might occur as a result of hypergastrinaemia as well as prevent an increase in parietal cell mass and in sensitivity of the parietal cells to secretagogue stimulation. The failure of nocloprost to enhance plasma gastrin levels was also observed in tests with 24h pH recording studies. In these tests, nocloprost was used three times daily before major meals, and continuous pH records were made during 24h examination. As shown in Figs. 3 and 4, the pH profile did not differ between placebo and nocloprost treatment, indicating that the agent does not interfere with the acid secretory activity of parietal cells. The increments in plasma gastrin after three major meals (breakfast, lunch, and dinner) were significantly lower in subjects treated with nocloprost than in those receiving placebo. These results suggest that the threshold for the inhibition of gastrin release by nocloprost is significantly lower than for the inhibition of acid secretion. Nocloprost has been reported to be useful in combination with NSAID therapy to prevent gastric mucosal damage (15). Such therapy is most likely due to the reduction in the PG biosynthesis in the gastric mucosa (24), so the successful use of nocloprost may be considered a ‘replacement’ therapy. In other conditions of reduced PG formation in the damaged gastric mucosa such as occurring in critically ill patients (burns, trauma, stress, etc.) nocloprost may also prove to be useful, particularly since this agent does not increase intragastric pH and thus may reduce the risk of bacterial overgrowth and sepsis (25).
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Nocloprost and Gastric Function REFERENCES 1. Thomas JM, Misiewicz G , Histamine H2-receptor antagonists in the short- and long-term treatment of duodenal ulcer. Clin Gastroenterol 1984, 13, 501542 2. Bardhan KD. Omeprazole in the management of refrectory duodenal ulcer. Scand J Gastroenterol 1989, 24(suppl 166), 63-73 3. Schwarz K, Beitz Z . Ueber penetriende magen und jejunalgeschwure. Klin Chir 1910, 67, 96-128 4. Sol1 AH. Peptic ulcer diseases. Perspectives on pathophysiology and therapy. J Clin Gastroenterol 1989, ll(supp1 1) 5. Rademaker JW, Hunt RH. Acid and barriers. Current research and future developments for peptic ulcer therapy. Scand J Gastroenterol1990,25(suppl 175) 6. Konturek SJ, Kwiecien N, Swierczek J , Oleksy J, Sito E, Robert A. Comparison of methylated prostaglandin E2 analogs given orally in the inhibition of gastric responses to pentagastrin and peptone meal in men. Gastroenterology 1976, 760, 683-687 7. Sol1 AH. Specific inhibition by prostaglandin E2 and 12 of histamine stimulated [“C] aminopyrine accumulation and cyclic adenosine monophosphate generation by isolated canine parietal cells. J Clin Invest 1980, 650, 1222-1229 8. Beinborn M, Netz S, Staar U , Sewing K-FR. Localization and characterization of prostaglandin E2 receptors in the porcine fundic mucosa Gastroenterology 1986, 90, 1343 9. Walt RP. Prostaglandins and peptic ulcer therapy. Scand J Gastroenterol 1990, 25(suppl 174), 29-36 10. Lanza FL, Aspinal RL, Swabb EA, Davis RE, Rack MF, Rubin A. A double blind placebo controlled effects of misoprostal and cimetidine on tolmetin induced gastric mucosal injury. Gastroenterology 1987, 92, 1491 11. Agrawal NM, Tulane V, Roth S. Misoprostol coadministration heals aspirin-induced gastric lesions in rheumatoid arthritis patients. Gastroenterology 1987, 92, 1290 12. Konturek SJ. Mechanisms of gastroprotection. Scand J Gastroenterol 1990, 25(suppl 174), 15-28 13. Losert W, Loge 0, Raduchel B, Skuballa W. Nocloprost. Drugs Fut 1986, 11, 660-662 Received 6 February 1991 Accepted 13 June 1991
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14. Konturek SJ, Brzozowski T, Drozdowicz D , et al. Nocloprost, a unique PGE2 analog with local gastroprotective and ulcer healing activity. Eur J Pharmacol 1991, 195, 247-357 15. Konturek SJ, Konturek JW, Kwiecien N, et al. Gastric protection by nocloprost against aspirin damage in humans. Scand J Gastroenterol 1991, 26, 231-236 16. George JD. New clinical method for measuring the rate of gastric emptying: the double sample test meal. Gut 1968, 8, 237-242 17. Konturek SJ, Kwiecien N, Obtulowicz W, Kopp B, Oleksy J, Rovati L. Cholecystokinin in the inhibition of gastric secretion and gastric emptying in humans. Digestion 1990, 45, 1-8 18. McLauchlan G , Rawlings JM, Lucas ML, McCloy RF, Crean GP, McColl KEL. Electrodes for 24 hour pH monitoring-a comparative study. Gut 1787,28, 935-939 19. Krawiec J , Pdes HS, Schwartz B, Lamprecht SA. Regional difference in ambient intraluminal gastric acidity after cimetidine monitored by intragastric pH-metry. Am J Gastroenterol 1983, 78, 272-275 20. Emde C, Garner A, Blum AL. Technical aspects of intraluminal pH-metry in man: current status and recommendations. Gut 1987, 28, 1177-1188 21. Gabryelewicz A, Kulesza E, Konturek SJ. Comparison of loxiglumide a cholecystokinin receptor antagonist and atropine on hormonal and meal stimulated pancreatic secretion in man. Scand J Gastroenterol 1990, 25, 731-738 22. Tabata K, Okade S. Gastric secretory conditions and plasma gastrin levels in rats after prolonged treatment with cometidine. Dig Dis Sci 1984, 29, 40-45 23. Lind T, Cederberg C, Olausson M, Olbe L. 24hour intragastric acidity and plasma gastrin after omeprazole and after proximal gastric vagotomy in duodenal ulcer patients. Gastroenterology 1990,99, 1593-1 599 24. Vane JR. Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 1971, 231, 232-235 25. Perr NJ. Cimetidine and gastrointestinal bleeding in critically ill patients. Gut 1986, 27, 122-123
ISSN: 0036-5521 (Print) 1502-7708 (Online) Journal homepage: http://www.tandfonline.com/loi/igas20
Effects of Nocloprost on Gastric Functions in Man S. J. Konturek, N. Kwiecien, W. Obtulowicz, J. Maczka, Z. Hebzda & J. Oleksy To cite this article: S. J. Konturek, N. Kwiecien, W. Obtulowicz, J. Maczka, Z. Hebzda & J. Oleksy (1991) Effects of Nocloprost on Gastric Functions in Man, Scandinavian Journal of Gastroenterology, 26:11, 1145-1151, DOI: 10.3109/00365529108998606 To link to this article: http://dx.doi.org/10.3109/00365529108998606
Published online: 08 Jul 2009.
Submit your article to this journal
View related articles
Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=igas20 Download by: [RMIT University Library]
Date: 04 April 2016, At: 00:25
Effects of Nocloprost on Gastric Functions in Man S. J . KONTUREK, N. KWIECIEN, W. OBTULOWICZ, J. MACZKA, 2. HEBZDA & J. OLEKSY Institute of Physiology, Academy of Medicine, Cracow, Poland
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Konturek SJ, Kwiecien N, Obtulowicz W, Maczka J , Hebzda Z , Oleksy J . Effects of nocloprost on gastric functions in man. Scand J Gastroenterol 1991,26, 1145-1151 Previous studies in animals and humans demonstrated that nocloprost, a stable prostaglandin E2analogue, shows very high gastroprotective potency, relatively weak gastric inhibitory activity, and low systemic bioavailability after oral administration. In this study the effects of nocloprost on gastric acid secretion and intraluminal pH and on gastric emptying and plasma gastrin levels were determined in humans. Nocloprost at doses of 50 and 100 pg was ineffective, but at a dose of 200 pg it reduced the response to pentagastrin significantly and that to a peptone meal by 30-S0% and abolished plasma gastrin response without affecting the rate of gastric emptying, Nocloprost given at a dose of 100 pg three times daily 30 min before the major meals (breakfast, lunch, and dinner) did not affect intragastric pH significantly as monitored by continuous intraluminal pH-metry. We conclude that nocloprost does not affect gastric acid secretion or intraluminal pH when applied at a dose (SO-100 pg) that is gastroprotective and that is proposed for peptic ulcer therapy. A higher dose (200 pg) of nocloprost causes moderate gastric acid inhibition and suppression of plasma gastrin release without affecting gastric emptying or causing any side effects. Key words: Gastric emptying; gastrin; prostaglandin; stomach
Prof. Dr. S. 1. Konturek, Institute of Physiology, 31-531 Krakow, ul. Grregorzecka 16. Poland
The therapeutic success of potent antisecretory drugs such as H2-receptor antagonists (H2RA) or omeprazole (1,2) supports the notion that acidpeptic activity plays a crucial role in the pathogenesis of peptic ulceration (3,4) and that the inhibition of this activity provides a favourable environment for ulcer healing ( 5 ) . Stable methylated analogues of prostaglandin El (PGE1) or PGE2 are potent direct inhibitors of gastric acid secretion (6) at a site close to the adenylate cyclase in parietal cells (7,s).By decreasing the acid output or intraluminal acid concentration these analogues can promote healing of gastroduodenal ulcerations (9) and minimize the mucosal damage by agents such as aspirin (10,ll). When viewed solely in terms of ability to suppress acid secretion, PGs do not offer any significant therapeutic advantages over H2RA (9). Several stable analogues have so far been proposed in the therapy of gastric mucosal disorders,
but actually only misoprostol and enprostil have been used clinically. The major drawback of PGs is that they are not superior to H2RA in peptic ulcer therapy, and they may cause some side effects such as diarrhoea and uterine contractions, excluding their use in pregnant women or during the child-bearing age. Thus, despite the welldocumented cytoprotective activity (12), the dinical use of PGs in gastric disorders is a t present rather limited (9-11). Attempts have been made to obtain PG derivatives that are without gastric antisecretory activity but retain gastroprotective and ulcer-healing effects without any potential hazards. Nocloprost is a PGE2 analogue that both in experimental animals (13,14) and in humans seems to fulfil the requirements of a clinically useful PG because of very low systemic bioavailability, relatively weak gastric antisecretory action, and predominantly local protective and ulcer-healing properties (15).
1146
S. J. Konturek et al.
This study was designed to explore in humans the effects of nocloprost on exocrine and endocrine gastric secretion and motility after oral administration at the dose range that was shown to be highly protective against aspirin damage in humans (15).
T
1
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MATERIALS AND METHODS Subjects Studies were carried out on 28 duodenal ulcer patients divided into 3 groups (A, B, and C), the mean age being 22 years (range, 19-23 years) and mean weight 74 kg (range, 68-77 kg). All subjects were in clinical remission, confirmed by endoscopy, when the study period began. Each patient gave informed consent, and the study was approved by Institutional Ethical Committee. All subjects were hospitalized, and 1week before the study all medication was withdrawn and alcohol was forbidden. Study design Three series of secretory tests were performed, each on a separate group of 8-10 subjects. Group A subjects were used for the secretory studies with pentagastrin infusion, group B subjects for studies with a peptone meal, and group C for studies with 24-h pH-metry. In tests with pentagastrin (2 pg/kg-h) infusion, gastric juice was collected after an overnight fast, by means of a standard aspiration technique using a double-lumen tube as described previously (6). The acidity of the juice was measured by titrating 0.2-ml samples with 100mM NaOH, using an automatic titrator (Autoburet, Radiometer, Copenhagen, Denmark). Acid outputs were expressed in millimoles per 15 min. Pepsin concentration was determined with a modification of the Anson haemoglobin method (6) and expressed as milligrams pepsin per milliliter by reading the trichloracetic acid supernatant spectrophotometrically at 280 nm and comparing the results with those of solutions incubated with different pepsin standards (hog pepsin, Pentex Biochemical, Kankakee, Ill., USA). Pepsin outputs were calculated taking into consideration the dilution of samples and expressed as milligrams pepsin per 15 min.
RANITIDINE 150 mgld a;i----+L--+--4, 1
CONTROL
1
W~AL
i
i
3
i
1Smin PERIODS Fig. 1 . Effects of nocloprost at doses of 50, 100, or 200 pg and ranitidine at dose of 150 mg on pentagastrinstimulated gastric acid and pepsin outputs. Means ? SEM of eight tests in eight subjects. Asterisks indicate significant ( P < 0.05) decrease below the control value.
Nocloprost, 9~-chloro-16,16-dimethyl PGE2, was supplied in tablets of 50 or 100 pg by Asche AG, Hamburg, Germany, as prostag1andin-Bcyclodextrin complex as clathrate to ensure better stability and water solubility of the compound. Placebo tablets of similar appearance were also provided by Asche AG. Each subject was studied five times separated by 4- to 5-day periods, receiving nocloprost at 50, 100, or 200 pg per dose during one period, 150 mg ranitidine (Glaxo, Ware, U.K.) or placebo during the other periods, with sequence randomized in a double-blind manner. In group B a double-lumen tube was introduced into the stomach of overnight-fasted subjects, and after complete gastric emptying, basal gastric acid secretion was obtained by suction-aspiration for 30 min. Two tablets of nocloprost (200 pg) or
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Nocloprost and Gastric Function
placebo were then given, the gastric aspiration was stopped for 30min, and then a liquid meal consisting of 8% peptone (Bactopeptone, Difco Lab., Detroit, Mich., USA) adjusted to pH 5.5 (with 1 M NaOH) was introduced into the stomach in a volume of 300 ml during each of four consecutive 30-min periods. The stomach was emptied completely before the administration of the next 300-ml meal. Phenol red (15 mg) was added to each meal, and its concentration was determined spectrophotometrically at pH 11, at a wavelength of 540 nm. Gastric content was continuously mixed by the aspiration-perfusion system, and the meal-stimulated acid secretion was measured by intragastric titration with end point of pH 5.5, using 50 mM NaOH as described previously (6). The gastric residual at the end of each 30min meal was measured with the phenol red dye dilution technique (16). Gastric emptying was expressed in percentage as the difference between the original amount of dye marker added to the meal at time 0 and its fraction remaining in the stomach at the end of each 30-min period (17). In group C subjects 24-h intragastric pH was continuously monitored with monocrystal antimony pH probe (Synectics, Sweden) connected to a portable microprocessor recording unit (Digitrapper, Synectics, Sweden) (18,19). The outer diameter of the electrode was 2.1 mm, and it was inserted through a nostril and positioned in the lower corpus region of the stomach (controlled fluoroscopically at the beginning of each test). The electrode was fixed on the cheek with a small piece of adhesive tape. The distance between the electrode tip and the nostril was kept constant in a given subject. The Digitrapper unit was easily carried around in a small bag. The investigation started at 1200 h and continued until 1200 h the next day. The menus for breakfast (B), lunch (L), and light dinner (D) were similar on each day. Each subject underwent two studies during which 24-h intragastric acidity was monitored, and nocloprost (100 Fg) or a placebo tablet was ingested about 30 min before each meal. Twenty-four hours of the measurement periods were analysed by means of a computer program (Gastrogram version 5.44, Gastrosoft Inc.,
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Sweden). From the data obtained, the summary report of 24-h intragastric pH recording and the cumulative percentage of the frequency distribution of various pHs could be determined in tests with placebo and nocloprost. For statistical evaluation the whole 24-h record was divided into periods with pH of 1-2, 2-3, 3-4, 4-5, 6-7, and 7-8 in tests with nocloprost or placebo. Assessments Blood samples were taken from the peripheral vein into tubes containing 2500 U aprotinin (Trasylol@,Bayer, Germany) and 0.5 mg of ethylenediaminetetraacetic acid (EDTA) before and at 30-min intervals in tests with peptone meal or before and 30 min after major meals in 24-h pHrecording tests. Plasma gastrin and pancreatic polypeptide (PP) were measured by specific radioimmunoassays as described previously (621). The assay systems were sufficiently sensitive to detect 1.5pM gastrin and 2.5 pM PP.
NOCLOPROST (2OOyg3 PEPTONE MEAL 1501
- 1 -E .- 15-
CONTROL 0
E E
----W'NOCLOPROST
S
1
2
3 k 30min PERIODS
S
Fig. 2. Effects of nocloprost (200 pg) on plasma gastrin and gastric acid responses to a 8% peptone meal. Means 2 SEM of 10 tests in 10 subjects. Asterisks indicate significant (P < 0.05) decrease below the control value.
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In all tests routine records of arterial blood pressure, pulse rate, and body temperature were made 30 min after the administration of nocloprost or placebo. All subjects were questioned concerning untoward gastrointestinal and other side effects and asked to report any alterations in bowel movements during the 24 h after the last treatment dose of nocloprost. Results are expressed as means k SEM. Analysis of variance or the Duncan multiple range test was used to evaluate significance between the experimental procedures. Differences with P < 0.05 were considered significant.
RESULTS Acid and pepsin outputs in response to intravenous infusion of pentagastrin alone and penta-
gastrin with nocloprost given orally at doses of 50, 100, or 200 yg are shown in Fig. 1. Nocloprost at 50 and 1OOyg was ineffective. At a dose of 200 pg nocloprost reduced acid outputs significantly, by about 30-40%. Ranitidine at 150 mg completely abolished the acid response to pentagastrin in these subjects. Pepsin outputs were also increased in response to pentagastrin infusion, but pretreatment with nocloprost at any dose used did not affect pepsin secretion. In contrast, ranitidine almost completely abolished the pepsin response to pentagastrin. lntragastric administration of 8% peptone meal caused about threefold increase in acid secretion over basal values (Fig. 2). Acid outputs were well sustained during the consecutive 30-min periods, reaching in the second 30-min meal about 12 mmol/30 min or about 75% of pentagastrin-
Fig. 3. Typical summary intragastric p H graph versus time, showing one-channel pH recording in the same subject treated with placebo or nocloprost (100 pg/dose) three times daily. Arrows indicate the ingestion of major meals, breakfast (B), lunch (L), and dinner (D), and the time of administration of placebo or nocloprost tablets before each meal. The inset above shows the summary pH and frequency distribution in the tests.
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Nocloprost and Gastric Function
induced maximal acid output (16.20 +- 3.28 mmol/30 min) in these subjects. Nocloprost administered in a dose of 200 pg before the meal reduced the acid response to peptone by about 35-50%. Gastric emptying of a peptone meal in control tests with placebo averaged about 64% of the marker (phenol red) added to the meal. In tests with nocloprost on average 55% of the marker added to the peptone meal was emptied into the duodenum. The difference in the emptying rate between tests with placebo and nocloprost was not significant. Plasma gastrin concentration was elevated twoto three-fold after the peptone meal, and the pretreatment with nocloprost significantly reduced this postprandial gastrin elevation (Fig. 2). Plasma PP increased from a basal value of about 15.5 5.3 pM to 65.2 12.4 pM after the meal, and this increment was also significantly reduced (to about 36.7 8.8 pM) by the pretreatment with nocloprost. The 24-h intragastric pH curves recorded in the same subject treated with placebo or nocloprost is shown in Fig. 3. Both with placebo and with nocloprost medication the normal circadian course of pH curves with typical rise after meals and low values during the nighttime were recorded. The frequency distribution of total 24-h recording of pH readings was similar in placebo
*
*
*
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Table I. Plasma gastrin concentrations after major meals in placebo-treated and nocloprost-treated subjects Plasma gastrin (pM) Placebo
Breakfast Lunch Dinner
Nocloprost
Before
After
Before
After
3724 41 5 3527
5624* 79* 8* 97211*
3925 34 7 3728
44*5’F 53 *8t 61 2 1 2 * t
*
*
* Significant (P < 0.05) increase above the value recorded before the meal. t Significant (P < 0.05) decrease below the corresponding value recorded in placebo-treated subjects.
and nocloprost treatment. The comparison of the values at all pH levels showed no statistically significant difference between placebo and nocloprost treatment (Fig. 4). Plasma gastrin concentrations showed typical increments after each major meal in placebo-treated subjects. In tests with nocloprost administration before each meal, the increments in plasma gastrin were significantly smaller (Table I). No symptoms or side effects were recorded at any dose of nocloprost used. In no instance was there any significant change in blood pressure, pulse rate, body temperature, or bowel movements.
0 PLACEBO NOCLOPROST
PH
Fig. 4.Cumulative percentage distribution of total pH recording in subjects receiving placebo or nocloprost (100 pg) tablets three times daily 30 min before each major meal. Means ? SEM of 10 tests in 10 subjects.
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DISCUSSION This study demonstrates that nocloprost, a novel PGE2 analogue, does not affect gastric acid and pepsin secretion at the doses (50-100 pg) that were found to protect the human stomach against aspirin damage (15) and that are used in peptic ulcer therapy. At the higher dose (2001.18) nocloprost resulted in the moderate inhibition of gastric acid secretion and in the suppression of gastrin release without affecting gastric emptying or causing any side effects. Previous studies in animals (13, 14) demonstrated that nocloprost given intragastrically is highly effective against various types of mucosal lesions, including ethanol, aspirin, taurocholate, or stress. The protective doses applied intragastrically failed to alter gastric acid secretion but increased gastric alkaline secretion and mucosal blood flow, suggesting that nocloprost is capable of activating local protective mechanisms without alterating acid secretion. Since duodenal administration of nocloprost was ineffective, and a labelled compound (3H-nocloprost) introduced into the gut appeared only in a small fraction in the peripheral blood, it was accepted that this PG analogue undergoes extensive degradation in the mucosa and the liver, resulting in a very low (about 2%) systemic bioavailability. These experimental studies indicate that nocloprost has a unique ability to act locally on the gastric mucosa and reaches the systemic circulation in the active form only in small amounts. This explains the high degree of dissociation between the protective effects and the systemic actions on other organs, so that nocloprost is virtually devoid of systemic PGE2-like side effects. Indeed, no side effects were observed in our subjects treated with nocloprost up to the dose of 200 pg. No changes in the blood pressure, pulse rate, or body temperature and no gastrointestinal symptoms such as diarrhoea were recorded in the subjects tested with nocloprost. It is of interest that the plasma gastrin and PP, which increased two- to three-fold after the peptone meal, were significantly suppressed by the pretreatment with nocloprost (Fig. 2). As the dose of nocloprost (200pg) used was shown in tests with pentagastrin to inhibit gastric acid se-
cretion, it was expected to cause a compensatory increase in basal or peptone-stimulated plasma gastrin due to the interruption of normal feedback suppression of the G-cells by low intragastric pH. The fact that nocloprost suppressed the plasma gastrin response to a meal could not be explained by its effect on gastric acid secretion and suggests that the inhibition of the postprandial gastric acid secretion by this PG is mediated, at least in part, by direct action on the gastrin-secreting G-cells. Thus nocloprost, unlike histamine H antagonists or omeprazole (22,23), does not potentiate but rather suppresses food-stimulated gastrin levels. This could prevent any rebound hypersecretion that might occur as a result of hypergastrinaemia as well as prevent an increase in parietal cell mass and in sensitivity of the parietal cells to secretagogue stimulation. The failure of nocloprost to enhance plasma gastrin levels was also observed in tests with 24h pH recording studies. In these tests, nocloprost was used three times daily before major meals, and continuous pH records were made during 24h examination. As shown in Figs. 3 and 4, the pH profile did not differ between placebo and nocloprost treatment, indicating that the agent does not interfere with the acid secretory activity of parietal cells. The increments in plasma gastrin after three major meals (breakfast, lunch, and dinner) were significantly lower in subjects treated with nocloprost than in those receiving placebo. These results suggest that the threshold for the inhibition of gastrin release by nocloprost is significantly lower than for the inhibition of acid secretion. Nocloprost has been reported to be useful in combination with NSAID therapy to prevent gastric mucosal damage (15). Such therapy is most likely due to the reduction in the PG biosynthesis in the gastric mucosa (24), so the successful use of nocloprost may be considered a ‘replacement’ therapy. In other conditions of reduced PG formation in the damaged gastric mucosa such as occurring in critically ill patients (burns, trauma, stress, etc.) nocloprost may also prove to be useful, particularly since this agent does not increase intragastric pH and thus may reduce the risk of bacterial overgrowth and sepsis (25).
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