Protection against aspirin-induced gastric lesions by lansoprazole: Simultaneous evaluation of functional and morphologic responses The protective effect of lansoprazole, a new proton pump inhibitor, against aspirin-induced gastric lesions was studied in a double-blind crossover trial with a simultaneous measure of the functional capacities of the mucosal barrier (by a recording of the gastric potential difference) and of the morphologic changes in the mucosa (by gastric endoscopy). After 1 week of treatment with lansoprazole (30 mg per day) or placebo, each healthy volunteer received 1 gm aspirin by mouth. Recording of the gastric potential difference lasted for 3 hours and was followed by gastric endoscopy. Morphologic lesions induced by aspirin were effectively prevented by lansoprazole: Lanza score was 0.67 ± 0.98 (mean ± SD) versus 2.25 ± 1.1 with placebo (p < 0.005, ANOVA). Conversely, the decrease in the gastric potential difference was similar. The inhibition of acid secretion induced by lansoprazole was therefore sufficient to prevent aspirin-induced mucosal lesions without reinforcing the defense capacities of the mucosa. This simple pharmacologic model makes it possible to simultaneously evaluate the functional and morphologic effects of aspirin intake on the gastric mucosa. (CLIN PHARMACOL THER 1992;52:413-6.)
Jean-Francois Bergmann, MD, Olivier Chassany, MD, Guy Simoneau, MD, Marc Lemaire, MD, Jean-Marc Segrestaa, MD, and Charles Caulin, MD, Paris, France
Aspirin is the most gastrotoxic of the anti-inflammatory drugs.' It provokes changes in the physicochemical properties of the mucosa, thereby inducing a disruption of the gastric mucosal barrier with an increase in luminal hydrogen ion (F1±) loss.2 This H+ retrodiffusion can be evaluated by the measurement of the gastric potential difference, which illustrates the ion flux across the mucosa. Aspirin induces H+ retrodiffusion and a decrease in gastric potential difference. Aspirin also results in macroscopic mucosal lesions linked to ischemic phenomena and characterized mainly by erosion, petechiae, and bleeding. These are best evaluated by gastric endoscopy.3
From the Therapeutics Research Unit, Lariboisiere Hospital, and Houde Laboratories, Paris La Defense. Supported by a grant from Houde Laboratories Paris La Defense Received for publication April 22, 1992; accepted June 11, 1992. Reprint requests: Jean-Francois Bergmann, MD, Clinique Therapeutique, Hopital Lariboisiere, 2 rue Ambroise Pare, 75010 Paris, France. 13/1/40209
Drugs that protect the gastric mucosa, especially antacids, prostaglandins, and sucralfate, reduce the retrodiffusion induced by aspirin and measured by gastric potential difference.4 Antisecretory agents such as H2-blockers seem to have a controversial effect on the retrodiffusion of H± ions because they induce a small increase in gastric potential difference.5 However, they effectively protect the gastric mucosa from lesions induced by aspirin and visualized by gastroscopy.6 This property may simply be the result of the decrease in acid secretion, which would prevent aspirin-induced microlesions from developing. To determine whether there was a correlation between the decrease in gastric potential difference and the extent of the endoscopic lesions, we measured the gastric potential difference and endoscopic Lanza score3 before and after aspirin intake in all the subjects participating in the study. We attempted to distinguish cytoprotective activity from antisecretory activity by taking these measurements after the administration of lansoprazole, a new potent proton pump inhibitor,' or placebo.
413
414
CLIN PHARMACOL THER OCTOBER 1992
Bergmann et al.
Table I. Gastric endoscopic Lanza scores (ranging from 0 [normal] to 4 [ulcer]) in 12 healthy volunteers after week of treatment with lansoprazole (30 mg) or placebo followed by intake of aspirin* Lansoprazole No. of subjects
Lanza score 0
0 4
2 3
*p
-±
SD
8% 8% 43% 33% 8%
1 1
33%
5
0 0
4
Mean Lanza score
Placebo No. of subjects 67%
8
1
4 1
0.67
-±
1
0.98
2.25
-±
1.1
0.5) was shown in the 24 simultaneous evaluations of gastric potential difference and gastroscopy after aspirin intake. No adverse clinical or biologic reaction was observed during the study. The pH measurement in six subjects confirmed the antisecretory effect of lansoprazole with a gastric pH above 4 in all cases, with a pH below 2 during the placebo period.
DISCUSSION This study confirms that the administration of lansoprazole, a potent antisecretory agent, makes it possible to prevent endoscopic lesions induced by aspirin. By eliminating gastric acidity, this proton pump inhibitor decreases the aggressivity of aspirin, facilitates impaired epithelial restitution, and reduces pepsin activity.8 These acid-dependent mechanisms are sufficient to prevent the development of petechiae and gastric erosion and to almost completely abolish gastric blood loss.9 We showed that, even after intake of the proton pump inhibitor, aspirin still has a toxic effect on the gastric mucosa with retrodiffusion of 1-1± ions and a decrease in gastric potential difference comparable to that observed when aspirin is administered after I week of placebo treatment. The bioavailability of Ian-
healthy
Placebo
p Value
± ± ± ± ±
NS NS NS NS NS
49.7 366.8 13.2 15.7 34.4
332.5 13.2 16.7 37.6
(1 gm) in 12
6.3 392.2 9.9 15.8
28.4
A, maximum decrease in GPD; t,a, time for
415
occurrence:
soprazole has a large interindividual variability.* But it cannot explain the variability in gastric potential difference measurements because, in our study, lansoprazole had a clear pharmacodynamic activity, as shown by the pH increase during the treatment with the proton pump inhibitor in all the subjects who had gastric potential difference and simultaneous pH recording. However, intersubject variability of gastric potential difference has been observed previously 1`) and may be related to large individual variability of the cytoprotective property of the gastric mucosa. There is a clear correlation between gastric potential difference and aspirin-induced ultrastructural changes in human gastric mucosa.11 This leads us to believe that even after an increase in intragastric pH, 1 gm aspirin induces a rupture of the mucosal barrier. However, when no acid is present, these microscopic structural and functional lesions cannot develop into macroscopic lesions that are visible during gastroscopy. 12 Furthermore, antisecretory agents increase gastric pH to values over 3.5, which is the pKa of aspirin, thereby reducing its level of absorption" without modifying the local mucosal aggression recorded by the gastric potential difference. This study shows that, in a single experimental model of gastric irritation, the functional and macroscopic effects on the mucosal membrane can be evaluated simultaneously: the former by measurement of the gastric potential difference and the latter by fibroscopic examination. The two mechanisms of irritation are independent,14"5 and lansoprazole prevents only one of the two. Potent antisecretory agents are the most effective drugs in the prevention of aspirin-induced endoscopic lesions,6 but for the gastric potential difference they are less effective than gastric coating agents or prostaglandins. 16 The latter
*Flouvat B. Houde pharrnacokinetics report, March 1990.
CLIN PHARMACOL THER OCTOBER 1992
416 Bergmann et al. effectively strengthen the mucosal barrier, but when used at doses that are not antisecretory, they are less effective in preventing hemorrhagic gastric lesions.17 In conclusion, it is possible to distinguish the functional and morphologic effects of a gastrotoxic drug such as aspirin during experimental studies in humans. Lansoprazole prevents hemorrhagic lesions without reinforcing the mucosal barrier. Our experimental model can be used in clinical pharmacology to evaluate the mechanism of action and the efficacy of drugs that protect the gastric mucosa.
References Aabakken L. Non-steroidal, antiinflammatory drugs. The excending scope of gastrointestinal scale effects. Aliment Pharmacol Ther 1992;6:143-62. Shea-Donohue T, Steel L, Montcalm-Mazzilli E, Dubois A. Aspirin-induced changes in gastric function: role of endogenous prostaglandins and mucosa] damage. Gastroenterology 1990;98:284-92. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980;303:136-8. Bergmann JF, Caulin C, Simoneau G, Dorf G, Segrestaa JM. Persistent gastric-protective effect of antacid evaluated by measurement of transmucosal gastric potential difference. CLIN PHARMACOL THER 1988;44:546-9. Read NW, Levin RJ. Cimetidine and gastric potential difference [Letter]. Lancet 1975;2:1314. Bigard MA, Isal JP. Complete prevention by omeprazole of aspirin-induced gastric lesions in healthy subjects [Abstract]. Gut 1988;29:A712. Satoh H, Inatomi N, Nagaya H, et al. Antisecretory and antiulcer activities of a novel proton pump inhibitor
AG-1749 in dogs and rats. J Pharmacol Exp Ther 1989;248:806-15. Black BA, Morris GP, Wallace JL. Effects of acid on the basal lamina of the rat stomach and duodenum. Wirchaw Arch (Cell Pathol) 1985;50:109-18. Daneshmend TK, Stein AG, Bhaskar NK, Hawley CJ. Abolition by omeprazole of aspirin-induced gastric mucosal injury in man. Gut 1990;31:514-7. Florent C, Pfeiffer A, Bernier JJ. La faiblesse de la barriere muqueuse: un nouveau concept. Gastroenterol Clin Biol 1985;9(suppl 12):65-71. Baskin WN, Kevin JI, Krause WJ, Jeffrey GE, Gemmel! RT. Aspirin-induced ultrastructural changes in human gastric mucosa: correlation with potential difference. Ann Intern Med 1976;85:299-303. Scheiman JM, Behler EM, Loeffler KM, Elta GH. Prophylaxis of aspirin induced gastroduodenal injury by omeprazole [Abstract]. Gastroenterology 1992;102: A160. Cooke AR, Hunt JM. Absorption of acetylsalicylic acid from unbuffered and buffered gastric contents. Am J Dig Dis 1970;15:95-102. Geppetti P, Tramontane M, Evangelista S, et al. Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 1991;101: 1505-11. Robert A, Leung FW, Guth PH. Morphological and functional gastric cytoprotection by prostaglandin in rats receiving absolute ethanol orally. Gut 1992;33:44451.
Florent C, Flourie B, Pfeifer A, Bernier JJ. Mesure de la difference de potentiel transepitheliale gastrique. Gastroenterol Clin Biol 1985;9(suppl 12):58-64. Hunt JN, Smith JL, Jiang CL, Kessler L. Effect of synthetic prostaglandin E, analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci l983;28:897902.
Jean-Francois Bergmann, MD, Olivier Chassany, MD, Guy Simoneau, MD, Marc Lemaire, MD, Jean-Marc Segrestaa, MD, and Charles Caulin, MD, Paris, France
Aspirin is the most gastrotoxic of the anti-inflammatory drugs.' It provokes changes in the physicochemical properties of the mucosa, thereby inducing a disruption of the gastric mucosal barrier with an increase in luminal hydrogen ion (F1±) loss.2 This H+ retrodiffusion can be evaluated by the measurement of the gastric potential difference, which illustrates the ion flux across the mucosa. Aspirin induces H+ retrodiffusion and a decrease in gastric potential difference. Aspirin also results in macroscopic mucosal lesions linked to ischemic phenomena and characterized mainly by erosion, petechiae, and bleeding. These are best evaluated by gastric endoscopy.3
From the Therapeutics Research Unit, Lariboisiere Hospital, and Houde Laboratories, Paris La Defense. Supported by a grant from Houde Laboratories Paris La Defense Received for publication April 22, 1992; accepted June 11, 1992. Reprint requests: Jean-Francois Bergmann, MD, Clinique Therapeutique, Hopital Lariboisiere, 2 rue Ambroise Pare, 75010 Paris, France. 13/1/40209
Drugs that protect the gastric mucosa, especially antacids, prostaglandins, and sucralfate, reduce the retrodiffusion induced by aspirin and measured by gastric potential difference.4 Antisecretory agents such as H2-blockers seem to have a controversial effect on the retrodiffusion of H± ions because they induce a small increase in gastric potential difference.5 However, they effectively protect the gastric mucosa from lesions induced by aspirin and visualized by gastroscopy.6 This property may simply be the result of the decrease in acid secretion, which would prevent aspirin-induced microlesions from developing. To determine whether there was a correlation between the decrease in gastric potential difference and the extent of the endoscopic lesions, we measured the gastric potential difference and endoscopic Lanza score3 before and after aspirin intake in all the subjects participating in the study. We attempted to distinguish cytoprotective activity from antisecretory activity by taking these measurements after the administration of lansoprazole, a new potent proton pump inhibitor,' or placebo.
413
414
CLIN PHARMACOL THER OCTOBER 1992
Bergmann et al.
Table I. Gastric endoscopic Lanza scores (ranging from 0 [normal] to 4 [ulcer]) in 12 healthy volunteers after week of treatment with lansoprazole (30 mg) or placebo followed by intake of aspirin* Lansoprazole No. of subjects
Lanza score 0
0 4
2 3
*p
-±
SD
8% 8% 43% 33% 8%
1 1
33%
5
0 0
4
Mean Lanza score
Placebo No. of subjects 67%
8
1
4 1
0.67
-±
1
0.98
2.25
-±
1.1
0.5) was shown in the 24 simultaneous evaluations of gastric potential difference and gastroscopy after aspirin intake. No adverse clinical or biologic reaction was observed during the study. The pH measurement in six subjects confirmed the antisecretory effect of lansoprazole with a gastric pH above 4 in all cases, with a pH below 2 during the placebo period.
DISCUSSION This study confirms that the administration of lansoprazole, a potent antisecretory agent, makes it possible to prevent endoscopic lesions induced by aspirin. By eliminating gastric acidity, this proton pump inhibitor decreases the aggressivity of aspirin, facilitates impaired epithelial restitution, and reduces pepsin activity.8 These acid-dependent mechanisms are sufficient to prevent the development of petechiae and gastric erosion and to almost completely abolish gastric blood loss.9 We showed that, even after intake of the proton pump inhibitor, aspirin still has a toxic effect on the gastric mucosa with retrodiffusion of 1-1± ions and a decrease in gastric potential difference comparable to that observed when aspirin is administered after I week of placebo treatment. The bioavailability of Ian-
healthy
Placebo
p Value
± ± ± ± ±
NS NS NS NS NS
49.7 366.8 13.2 15.7 34.4
332.5 13.2 16.7 37.6
(1 gm) in 12
6.3 392.2 9.9 15.8
28.4
A, maximum decrease in GPD; t,a, time for
415
occurrence:
soprazole has a large interindividual variability.* But it cannot explain the variability in gastric potential difference measurements because, in our study, lansoprazole had a clear pharmacodynamic activity, as shown by the pH increase during the treatment with the proton pump inhibitor in all the subjects who had gastric potential difference and simultaneous pH recording. However, intersubject variability of gastric potential difference has been observed previously 1`) and may be related to large individual variability of the cytoprotective property of the gastric mucosa. There is a clear correlation between gastric potential difference and aspirin-induced ultrastructural changes in human gastric mucosa.11 This leads us to believe that even after an increase in intragastric pH, 1 gm aspirin induces a rupture of the mucosal barrier. However, when no acid is present, these microscopic structural and functional lesions cannot develop into macroscopic lesions that are visible during gastroscopy. 12 Furthermore, antisecretory agents increase gastric pH to values over 3.5, which is the pKa of aspirin, thereby reducing its level of absorption" without modifying the local mucosal aggression recorded by the gastric potential difference. This study shows that, in a single experimental model of gastric irritation, the functional and macroscopic effects on the mucosal membrane can be evaluated simultaneously: the former by measurement of the gastric potential difference and the latter by fibroscopic examination. The two mechanisms of irritation are independent,14"5 and lansoprazole prevents only one of the two. Potent antisecretory agents are the most effective drugs in the prevention of aspirin-induced endoscopic lesions,6 but for the gastric potential difference they are less effective than gastric coating agents or prostaglandins. 16 The latter
*Flouvat B. Houde pharrnacokinetics report, March 1990.
CLIN PHARMACOL THER OCTOBER 1992
416 Bergmann et al. effectively strengthen the mucosal barrier, but when used at doses that are not antisecretory, they are less effective in preventing hemorrhagic gastric lesions.17 In conclusion, it is possible to distinguish the functional and morphologic effects of a gastrotoxic drug such as aspirin during experimental studies in humans. Lansoprazole prevents hemorrhagic lesions without reinforcing the mucosal barrier. Our experimental model can be used in clinical pharmacology to evaluate the mechanism of action and the efficacy of drugs that protect the gastric mucosa.
References Aabakken L. Non-steroidal, antiinflammatory drugs. The excending scope of gastrointestinal scale effects. Aliment Pharmacol Ther 1992;6:143-62. Shea-Donohue T, Steel L, Montcalm-Mazzilli E, Dubois A. Aspirin-induced changes in gastric function: role of endogenous prostaglandins and mucosa] damage. Gastroenterology 1990;98:284-92. Lanza FL, Royer GL, Nelson RS. Endoscopic evaluation of the effects of aspirin, buffered aspirin and enteric-coated aspirin on gastric and duodenal mucosa. N Engl J Med 1980;303:136-8. Bergmann JF, Caulin C, Simoneau G, Dorf G, Segrestaa JM. Persistent gastric-protective effect of antacid evaluated by measurement of transmucosal gastric potential difference. CLIN PHARMACOL THER 1988;44:546-9. Read NW, Levin RJ. Cimetidine and gastric potential difference [Letter]. Lancet 1975;2:1314. Bigard MA, Isal JP. Complete prevention by omeprazole of aspirin-induced gastric lesions in healthy subjects [Abstract]. Gut 1988;29:A712. Satoh H, Inatomi N, Nagaya H, et al. Antisecretory and antiulcer activities of a novel proton pump inhibitor
AG-1749 in dogs and rats. J Pharmacol Exp Ther 1989;248:806-15. Black BA, Morris GP, Wallace JL. Effects of acid on the basal lamina of the rat stomach and duodenum. Wirchaw Arch (Cell Pathol) 1985;50:109-18. Daneshmend TK, Stein AG, Bhaskar NK, Hawley CJ. Abolition by omeprazole of aspirin-induced gastric mucosal injury in man. Gut 1990;31:514-7. Florent C, Pfeiffer A, Bernier JJ. La faiblesse de la barriere muqueuse: un nouveau concept. Gastroenterol Clin Biol 1985;9(suppl 12):65-71. Baskin WN, Kevin JI, Krause WJ, Jeffrey GE, Gemmel! RT. Aspirin-induced ultrastructural changes in human gastric mucosa: correlation with potential difference. Ann Intern Med 1976;85:299-303. Scheiman JM, Behler EM, Loeffler KM, Elta GH. Prophylaxis of aspirin induced gastroduodenal injury by omeprazole [Abstract]. Gastroenterology 1992;102: A160. Cooke AR, Hunt JM. Absorption of acetylsalicylic acid from unbuffered and buffered gastric contents. Am J Dig Dis 1970;15:95-102. Geppetti P, Tramontane M, Evangelista S, et al. Differential effect on neuropeptide release of different concentrations of hydrogen ions on afferent and intrinsic neurons of the rat stomach. Gastroenterology 1991;101: 1505-11. Robert A, Leung FW, Guth PH. Morphological and functional gastric cytoprotection by prostaglandin in rats receiving absolute ethanol orally. Gut 1992;33:44451.
Florent C, Flourie B, Pfeifer A, Bernier JJ. Mesure de la difference de potentiel transepitheliale gastrique. Gastroenterol Clin Biol 1985;9(suppl 12):58-64. Hunt JN, Smith JL, Jiang CL, Kessler L. Effect of synthetic prostaglandin E, analog on aspirin-induced gastric bleeding and secretion. Dig Dis Sci l983;28:897902.
