0 1990 Raven Press, Ltd., New York
J Clin Gnstroenrerol 1990;12(3):267-70
Chronic @Carotene Supplementation Does Not Alter the Gastric Mucosal Response to Acute Aspirin Ingestion Frank M. Moses, M.D.,J. Walter Kikendall, M.D.,Phyllis Bowen, T. R. Young, M . S .
Ph.D.,
and
Retinoids and carotenoids have been reported since 1967 to be important in maintaining gastrointestinal tract mucous secretion and cell integrity in the face of irritants or injury (1,2). In humans, these compounds reduce gastrointestinal bleeding due to stress and indomethacin and improve healing of gastric ulcers (3-6). Animal studies have also suggested that retinoids and/or carotenoids may prevent drug-induced gastric lesions and cysteamineinduced duodenal ulcers (7-10). Since p-carotene is inexpensive and without known harmful side effects, confirmation of gastric mucosal protective effects of this micronutrient might lead to its use for selected prophylactic indications. Endoscopic documentation of the effects of aspirin upon the gastric mucosa has been standardized. Medication dosages of 650 mg one to four times per day induce reproducible gastric mucosal lesions occurring from 1 to 4 h after ingestion (1 1,12). We therefore designed a prospective, doubleblind study to evaluate endoscopically the effect of chronic p-carotene supplementation on acute aspirin mucosal injury.
Carotenoids and retinoids have been reported to reduce gastrointestinal mucosa damage from a variety of irritants. W e performed double-blind, placebo-controlled endoscopic trial to evaluate the effect of chronic pcarotene supplementation upon the gastric mucosal response to acute aspirin injury. Six subjects taking chronic p-carotene and six taking placebo each ingested 650 mg of aspirin after an endoscopy confirmed normal gastric mucosa. Three hours later, mucosal lesions were counted at repeat endoscopy. p-Carotene did not prevent acute mucosal injury better than placebo. Key Words: p-Carotene-Gastric cytoprotection-Aspirin.
MATERIALS AND METHODS Study Population Only current participants in an adenoma recurrence risk-reduction clinical trial were asked to participate in this aspirin study. Subjects were aged 45 to 70 years and each had been taking either placebo or p-carotene 15 mg p.0. daily for at least 6 months, administered in doubleblinded fashion as per the terms of the adenoma trial. Subjects had been excluded from the adenoma trial for premenopausal state, active alcoholism, o r history of hepatic or renal disease. Subjects were excluded from the aspirin trial for previous documentation of gastroduodenal ulcer disease, previous gastroduodenal surgery, use of chronic medications (except as noted), allergy or contraindication to aspirin therapy, or contraindication to performance of upper endoscopy. The protocol was ap-
From the Gastroenterology Service, Walter Reed Army Medical Center, Washington, D.C. (F.M.M., J.W.K.), Department
of Nutrition and Medical Dietetics, University of Illinois, Chicago, Illinois (P.B.) and Department of Clinical Investigation, Walter Reed Army Medical Center (T.R.Y.). Address correspondence and reprint requests to Dr. F. M. Moses at Gastroenterology Service, WRAMC, Washington, D.C. 20307-5001, U.S.A. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
267
F . M . MOSES ET AL.
268
TABLE 1. Effect of p-carotene upon aspirin-induced gastric lesions Control ( N = 6) Baseline Antrum Fundus Total
0.5 (0.8) 4.7 (3.9) 4.2 (4.8) 8.9 (8.11
p-Carotene ( N = 6) 0.7 (0.5) 5.5 (3.8) 6.5 (6.8) 12.0(7.51
Gastric mucosal endoscopic lesion count 3 h after aspirin ingestion, with standard deviation in parentheses. Baseline score is total antral and fundic lesions before aspirin ingestion. All lesions were submucosal hemorrhage. There is no statistically significant difference between control and p-carotene-treated subjects for any location.
proved by the Clinical Investigation and Human Use Subcommittees of the Department of Clinical Investigation.
Methods Adenoma study protocol patients who met entry criteria for the aspirin study and gave informed consent completed an entry questionnaire to screen for qualifications and to correlate with endoscopic findings. A routine upper endoscopy was then performed. If baseline endoscopy revealed more than a single subepithelial hemorrhage, the patient was disqualified from further participation. Three of 15 subjects entered into the study were excluded prior to administration of aspirin because of abnormal baseline upper endoscopy. The remaining 12 subjects were each given a single 650 mg oral dose of aspirin dissolved in 60 ml of water. Three hours after ingestion, a serum salicylate level was obtained and repeat upper endoscopy performed. The gastric mucosa was evaluated by two independent observers and graded by counting the total number of mucosal lesions within the antrum and fundus. Serum p-carotene and retinol had been analyzed within the previous month as part of the adenoma trial and were assumed to be stable.
Statistical Analysis The absolute numbers of gastric mucosal lesions were evaluated using the Wilkes-Shapiro and Student’s t tests.
RESULTS Fortuitously, the 12 subjects who completed this study consisted of 6 who had been taking @-carotene and 6 who had been taking placebo in the adenoma trial. The subjects receiving placebo and @-carotene were similar in sex distribution (five men, one woman), mean age (65 years, range of 54-74 years for placebo versus 60 years, range of 51-73 years for the @-carotene),and baseline endoscopic lesion count (0.5 versus 0.7) (Table 1). One control subject took hydrochlorothiazide. Two @carotene-treated subjects took hydrochlorothiazide, one took potassium chloride (Klorvess), and one timolol (Tirnoptic) eyedrops. The mean p-carotene level (? SEM) for the control was 15.9 k 3.6 pgidl and for the treatment group was 154.3 ? 48 pgidl, showing adequate treatment effects. Three hours posttreatment, the serum salicylate level (iSEM) of the control group was 3.9 k 0.6 mgidl compared to 5.2 +- 1.1 mg/dl for the pcarotene group. The 3 h postaspirin endoscopy lesion count in the antrum, fundus, and total stomach is seen in Fig. 1. All lesions seen were subepithelial hemorrhages; no erosions or ulcerations were noted. Subjects treated with p-carotene had higher lesion counts for the antrurn (5.5 versus 4.71, fundus (6.5 versus 4.2), and total gastric mucosa (12.0 versus 8.9). These differences were not statistically significant.
MUGOSAL LESIONS
1 12
FIG. 1. Effect of p-carotene ( @ , n
= 6) upon aspirin-induced gastric lesions. Baseline score is total antral and fundic lesion count before aspirin ingestion. Antrum, fundus, and total represent score postaspirin ingestion. Y axis represents mean number of mucosal lesions seen. B,control (n = 6). Scores are as follows: Baseline; controls 0.5, p-carotene 0.7. Antrum; controls 4.7, p-carotene 5.5. Fundus; controls 4.2, p-carotene 6.5. Total; controls 8.8, p-carotene 12.
10 8 6
4 2 0
BASELINE
ANTRUM
J Clin Gasfroenterol, Vol. 12, No. 3, 1990
FUNDUS
TOTAL
p-CAROTENE AND GASTRIC MUCOSAL RESPONSE TO ASPIRIN After 12 subjects were entered, the results were analyzed in an effort to determine the probability that a type I1 error had occurred. If the p-carotene treatment in reality reduced the mean number of aspirin-induced mucosal lesions by 50%, then the probability of observing an increase rather than a decrease in the mean number of lesions (of both the antrum and fundus) from 8.9 to 12.0 was p < 0.05. The trial was thus discontinued. DISCUSSION
Retinol and p-carotene are naturally occurring compounds with known physiologic functions that have been proposed as gastric mucosal protective agents (1,2). In research published in Hungary in both humans and experimental animals, vitamin A prevented the development of gastric mucosal damage after intragastric administration of injurious agents such as nonsteroidal anti-inflammatory drugs, aspirin, acid, and alcohol (3-9). Mucosal improvement was assessed by direct observation of the mucosa, alterations in mucosal enzyme content, reduction in gastric aspirate hemoglobin, and endoscopic observation of ulcer healing. Except as noted (1,2), these reports from Hungary remain unconfirmed; a study using a rat model of restraintinduced stress found no protective effect in the occurrence of gastric ulceration by pretreatment with 10,000 IU of vitamin A (13). Our study endoscopically evaluated the effect of chronic p-carotene supplementation on the acute reaction of the gastric mucosa to aspirin ingestion. The study was designed to recognize a 50% improvement in endoscopic scoring in the p-carotenetreated group. Because the initial results appeared to be uniform, the code was broken by the statistician after 12 subjects had been enrolled. Interval analysis of our results showed that although the groups were comparable demographically, had appropriate levels of carotene supplementation, and had similar salicylate levels, no improvement in endoscopic scoring was achieved when the p-carotene-treated group was compared to control subjects. The probability of observing these results, given the primary hypothesis, was sufficiently low ( p < 0.05) that the study was terminated. We concluded that chronic oral p-carotene does not protect against this form of acute gastric mucosal damage induced by aspirin. Our data are at variance with published Hungarian studies. With few exceptions, previous investigators administered the retinoid/carotenoid immediately prior to the mucosal irritant. In contrast, our
269
subjects had been on chronic supplementation but did not take the supplement on the day of the experiment. Second, several other studies employed dosages much higher than we tested (6,9), so that we may have missed a dose-dependent mucosal protective effect of p-carotene. Third, we did not study the gastric mucosal adaptation response that occurs during the first 5 to 7 days of continued aspirin ingestion (12). Although most experimental animal work was acute, it is conceivable that the protective effect of carotenoids observed by others involves alteration in this response. Finally, we did not study patients deficient in either retinol or carotenoids or patients with known peptic ulcer disease, so that we are unable to make any conclusion in regards to the effect of aspirin upon those subgroups. However, were carotenoids effective mucosal protectors, chronic daily supplementation would be the probable form of therapy. The dose we employed is just below the threshold for producing obvious carotenodermia, so that higher dosages would likely be unacceptable to many subjects. Despite chronic ingestion of a maximally tolerable dose, all our subjects developed subepithelial hemorrhages, typical manifestations of acute aspirin damage and thought to be precursors of gastric erosions (14,15). If retinoids and carotenoids beneficially altered mucosal permeability and cell wall integrity, they would be expected to have shown a benefit in this endoscopic study. In conclusion, the subjects who took p-carotene for greater than 6 months and had appropriate serum levels received no gastric mucosal protective effects from acute aspirin ingestion when measured by this endoscopic model. It appears unlikely that p-carotene supplementation alters the acute response of the gastric mucosa to aspirin ingestion, and it is premature to suggest p-carotene as mucosal protective therapy in patients taking aspirin or nonsteroidal anti-inflammatory drugs. REFERENCES I . Martin MS, Lambert R , Martin F. Effet protecteur de la vitamine A sur l’ulcere de contrainte du rat. C R Soc B i d (Paris) 1967;161:2527-30. 2. Chernov MS, Hale HW, Wood M. Prevention of stress ulcers. Am J Surg 1971;122:67&7. 3. Mozsik G , Moron F, Nagy L, Ruzsa CS, Tarnok F, Javor T. Evidence of the gastric cytoprotective effects of vitamin A, atropine and cimetidine on the development of gastric mucosal damage produced by administration of indomethacin in healthy subjects. Znt J Tissue React 1986;8:85-90. 4. Patty I , Benedek S, Deak G, et al. Controlled trial of vitamin A therapy in gastric ulcer. Lancet 1982;2:876. 5 . Patty I, Tarnok F, Simon L , et al. A comparative dynamic
J Clin Gustrornterol, Vol. 12, N o . 3, 1990
270
F . M . MOSES ET AL.
study of the effectiveness of gastric cytoprotection by vitamin A , de-nol, sucralfate and ulcer healing by pirenzepine in patients with chronic gastric ulcer (a multiclinical and randomized study). Acta Physiol Hung 1984;64:379-84. Javor T, Bata M, Lovasz L , et al. Gastric cytoprotective effects of vitamin A and other carotenoids. Znt J Tissue React 1983;5:289-96. Mozsik G , Javor T, Toth Gy, Zsoldos T , Tigyi A . Interrelationships between the gastric cytoprotective effects of vitamin A and beta carotene and the gastric mucosal superoxide dismutase activity in rats. Acta Physiol Hung 1984;64:315-8. Javor T, Tarnok F , Past T, Nagy S. Cytoprotective effect of free radical scavengers against mucosal damage produced by different antirheumatic drugs. Int J Tissue React 1986;8:3540. Mozsik G, Bata M, Fiegler M, et al. Interrelationships between the membrane-bound ATP-dependent energy systems of the gastric mucosa and the gastric cytoprotective effect of beta carotene on the development of gastric muco-
J Clin Gastroenterol, Vol. 12, No. 3, 1990
10.
11.
12.
13.
14.
15.
sal damage produced by 0.6 M HCI in rats. Acta Physiol Hung 1984;64:301-7. Mahmood T, Tenenbaum S, Niu XT, Levenson SM, Seifter E, Demetriou AA. Prevention of duodenal ulcer formation in the rat by dietary vitamin A supplementation. J Parenter Enter Nutr 1986;10:747. Graham DY, Smith JL. Effects of aspirin and an aspirinacetaminophen combination on the gastric mucosa in normal subjects. Gastroenterology 1985;88:1922-5. Graham DY, Smith J L , Spjut HJ, Torres E. Gastric adaptation: studies in humans during continuous aspirin administration. Gastroenterology 1988;95:327-33. Rasche R, Butterfield WC. Vitamin A pretreatment of stress ulcers in rats. Arch Surg 1973;106:32&1. Holt KM, Hollander D. Acute gastric mucosal injury: pathogenesis and therapy. Annu Rev Med 1986;37:107-24. Laine L, Weinstein WM. Subepithelial hemorrhages and erosions of human stomach. Dig Dis Sci 1988;33:49&503.
J Clin Gnstroenrerol 1990;12(3):267-70
Chronic @Carotene Supplementation Does Not Alter the Gastric Mucosal Response to Acute Aspirin Ingestion Frank M. Moses, M.D.,J. Walter Kikendall, M.D.,Phyllis Bowen, T. R. Young, M . S .
Ph.D.,
and
Retinoids and carotenoids have been reported since 1967 to be important in maintaining gastrointestinal tract mucous secretion and cell integrity in the face of irritants or injury (1,2). In humans, these compounds reduce gastrointestinal bleeding due to stress and indomethacin and improve healing of gastric ulcers (3-6). Animal studies have also suggested that retinoids and/or carotenoids may prevent drug-induced gastric lesions and cysteamineinduced duodenal ulcers (7-10). Since p-carotene is inexpensive and without known harmful side effects, confirmation of gastric mucosal protective effects of this micronutrient might lead to its use for selected prophylactic indications. Endoscopic documentation of the effects of aspirin upon the gastric mucosa has been standardized. Medication dosages of 650 mg one to four times per day induce reproducible gastric mucosal lesions occurring from 1 to 4 h after ingestion (1 1,12). We therefore designed a prospective, doubleblind study to evaluate endoscopically the effect of chronic p-carotene supplementation on acute aspirin mucosal injury.
Carotenoids and retinoids have been reported to reduce gastrointestinal mucosa damage from a variety of irritants. W e performed double-blind, placebo-controlled endoscopic trial to evaluate the effect of chronic pcarotene supplementation upon the gastric mucosal response to acute aspirin injury. Six subjects taking chronic p-carotene and six taking placebo each ingested 650 mg of aspirin after an endoscopy confirmed normal gastric mucosa. Three hours later, mucosal lesions were counted at repeat endoscopy. p-Carotene did not prevent acute mucosal injury better than placebo. Key Words: p-Carotene-Gastric cytoprotection-Aspirin.
MATERIALS AND METHODS Study Population Only current participants in an adenoma recurrence risk-reduction clinical trial were asked to participate in this aspirin study. Subjects were aged 45 to 70 years and each had been taking either placebo or p-carotene 15 mg p.0. daily for at least 6 months, administered in doubleblinded fashion as per the terms of the adenoma trial. Subjects had been excluded from the adenoma trial for premenopausal state, active alcoholism, o r history of hepatic or renal disease. Subjects were excluded from the aspirin trial for previous documentation of gastroduodenal ulcer disease, previous gastroduodenal surgery, use of chronic medications (except as noted), allergy or contraindication to aspirin therapy, or contraindication to performance of upper endoscopy. The protocol was ap-
From the Gastroenterology Service, Walter Reed Army Medical Center, Washington, D.C. (F.M.M., J.W.K.), Department
of Nutrition and Medical Dietetics, University of Illinois, Chicago, Illinois (P.B.) and Department of Clinical Investigation, Walter Reed Army Medical Center (T.R.Y.). Address correspondence and reprint requests to Dr. F. M. Moses at Gastroenterology Service, WRAMC, Washington, D.C. 20307-5001, U.S.A. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of the Army or the Department of Defense.
267
F . M . MOSES ET AL.
268
TABLE 1. Effect of p-carotene upon aspirin-induced gastric lesions Control ( N = 6) Baseline Antrum Fundus Total
0.5 (0.8) 4.7 (3.9) 4.2 (4.8) 8.9 (8.11
p-Carotene ( N = 6) 0.7 (0.5) 5.5 (3.8) 6.5 (6.8) 12.0(7.51
Gastric mucosal endoscopic lesion count 3 h after aspirin ingestion, with standard deviation in parentheses. Baseline score is total antral and fundic lesions before aspirin ingestion. All lesions were submucosal hemorrhage. There is no statistically significant difference between control and p-carotene-treated subjects for any location.
proved by the Clinical Investigation and Human Use Subcommittees of the Department of Clinical Investigation.
Methods Adenoma study protocol patients who met entry criteria for the aspirin study and gave informed consent completed an entry questionnaire to screen for qualifications and to correlate with endoscopic findings. A routine upper endoscopy was then performed. If baseline endoscopy revealed more than a single subepithelial hemorrhage, the patient was disqualified from further participation. Three of 15 subjects entered into the study were excluded prior to administration of aspirin because of abnormal baseline upper endoscopy. The remaining 12 subjects were each given a single 650 mg oral dose of aspirin dissolved in 60 ml of water. Three hours after ingestion, a serum salicylate level was obtained and repeat upper endoscopy performed. The gastric mucosa was evaluated by two independent observers and graded by counting the total number of mucosal lesions within the antrum and fundus. Serum p-carotene and retinol had been analyzed within the previous month as part of the adenoma trial and were assumed to be stable.
Statistical Analysis The absolute numbers of gastric mucosal lesions were evaluated using the Wilkes-Shapiro and Student’s t tests.
RESULTS Fortuitously, the 12 subjects who completed this study consisted of 6 who had been taking @-carotene and 6 who had been taking placebo in the adenoma trial. The subjects receiving placebo and @-carotene were similar in sex distribution (five men, one woman), mean age (65 years, range of 54-74 years for placebo versus 60 years, range of 51-73 years for the @-carotene),and baseline endoscopic lesion count (0.5 versus 0.7) (Table 1). One control subject took hydrochlorothiazide. Two @carotene-treated subjects took hydrochlorothiazide, one took potassium chloride (Klorvess), and one timolol (Tirnoptic) eyedrops. The mean p-carotene level (? SEM) for the control was 15.9 k 3.6 pgidl and for the treatment group was 154.3 ? 48 pgidl, showing adequate treatment effects. Three hours posttreatment, the serum salicylate level (iSEM) of the control group was 3.9 k 0.6 mgidl compared to 5.2 +- 1.1 mg/dl for the pcarotene group. The 3 h postaspirin endoscopy lesion count in the antrum, fundus, and total stomach is seen in Fig. 1. All lesions seen were subepithelial hemorrhages; no erosions or ulcerations were noted. Subjects treated with p-carotene had higher lesion counts for the antrurn (5.5 versus 4.71, fundus (6.5 versus 4.2), and total gastric mucosa (12.0 versus 8.9). These differences were not statistically significant.
MUGOSAL LESIONS
1 12
FIG. 1. Effect of p-carotene ( @ , n
= 6) upon aspirin-induced gastric lesions. Baseline score is total antral and fundic lesion count before aspirin ingestion. Antrum, fundus, and total represent score postaspirin ingestion. Y axis represents mean number of mucosal lesions seen. B,control (n = 6). Scores are as follows: Baseline; controls 0.5, p-carotene 0.7. Antrum; controls 4.7, p-carotene 5.5. Fundus; controls 4.2, p-carotene 6.5. Total; controls 8.8, p-carotene 12.
10 8 6
4 2 0
BASELINE
ANTRUM
J Clin Gasfroenterol, Vol. 12, No. 3, 1990
FUNDUS
TOTAL
p-CAROTENE AND GASTRIC MUCOSAL RESPONSE TO ASPIRIN After 12 subjects were entered, the results were analyzed in an effort to determine the probability that a type I1 error had occurred. If the p-carotene treatment in reality reduced the mean number of aspirin-induced mucosal lesions by 50%, then the probability of observing an increase rather than a decrease in the mean number of lesions (of both the antrum and fundus) from 8.9 to 12.0 was p < 0.05. The trial was thus discontinued. DISCUSSION
Retinol and p-carotene are naturally occurring compounds with known physiologic functions that have been proposed as gastric mucosal protective agents (1,2). In research published in Hungary in both humans and experimental animals, vitamin A prevented the development of gastric mucosal damage after intragastric administration of injurious agents such as nonsteroidal anti-inflammatory drugs, aspirin, acid, and alcohol (3-9). Mucosal improvement was assessed by direct observation of the mucosa, alterations in mucosal enzyme content, reduction in gastric aspirate hemoglobin, and endoscopic observation of ulcer healing. Except as noted (1,2), these reports from Hungary remain unconfirmed; a study using a rat model of restraintinduced stress found no protective effect in the occurrence of gastric ulceration by pretreatment with 10,000 IU of vitamin A (13). Our study endoscopically evaluated the effect of chronic p-carotene supplementation on the acute reaction of the gastric mucosa to aspirin ingestion. The study was designed to recognize a 50% improvement in endoscopic scoring in the p-carotenetreated group. Because the initial results appeared to be uniform, the code was broken by the statistician after 12 subjects had been enrolled. Interval analysis of our results showed that although the groups were comparable demographically, had appropriate levels of carotene supplementation, and had similar salicylate levels, no improvement in endoscopic scoring was achieved when the p-carotene-treated group was compared to control subjects. The probability of observing these results, given the primary hypothesis, was sufficiently low ( p < 0.05) that the study was terminated. We concluded that chronic oral p-carotene does not protect against this form of acute gastric mucosal damage induced by aspirin. Our data are at variance with published Hungarian studies. With few exceptions, previous investigators administered the retinoid/carotenoid immediately prior to the mucosal irritant. In contrast, our
269
subjects had been on chronic supplementation but did not take the supplement on the day of the experiment. Second, several other studies employed dosages much higher than we tested (6,9), so that we may have missed a dose-dependent mucosal protective effect of p-carotene. Third, we did not study the gastric mucosal adaptation response that occurs during the first 5 to 7 days of continued aspirin ingestion (12). Although most experimental animal work was acute, it is conceivable that the protective effect of carotenoids observed by others involves alteration in this response. Finally, we did not study patients deficient in either retinol or carotenoids or patients with known peptic ulcer disease, so that we are unable to make any conclusion in regards to the effect of aspirin upon those subgroups. However, were carotenoids effective mucosal protectors, chronic daily supplementation would be the probable form of therapy. The dose we employed is just below the threshold for producing obvious carotenodermia, so that higher dosages would likely be unacceptable to many subjects. Despite chronic ingestion of a maximally tolerable dose, all our subjects developed subepithelial hemorrhages, typical manifestations of acute aspirin damage and thought to be precursors of gastric erosions (14,15). If retinoids and carotenoids beneficially altered mucosal permeability and cell wall integrity, they would be expected to have shown a benefit in this endoscopic study. In conclusion, the subjects who took p-carotene for greater than 6 months and had appropriate serum levels received no gastric mucosal protective effects from acute aspirin ingestion when measured by this endoscopic model. It appears unlikely that p-carotene supplementation alters the acute response of the gastric mucosa to aspirin ingestion, and it is premature to suggest p-carotene as mucosal protective therapy in patients taking aspirin or nonsteroidal anti-inflammatory drugs. REFERENCES I . Martin MS, Lambert R , Martin F. Effet protecteur de la vitamine A sur l’ulcere de contrainte du rat. C R Soc B i d (Paris) 1967;161:2527-30. 2. Chernov MS, Hale HW, Wood M. Prevention of stress ulcers. Am J Surg 1971;122:67&7. 3. Mozsik G , Moron F, Nagy L, Ruzsa CS, Tarnok F, Javor T. Evidence of the gastric cytoprotective effects of vitamin A, atropine and cimetidine on the development of gastric mucosal damage produced by administration of indomethacin in healthy subjects. Znt J Tissue React 1986;8:85-90. 4. Patty I , Benedek S, Deak G, et al. Controlled trial of vitamin A therapy in gastric ulcer. Lancet 1982;2:876. 5 . Patty I, Tarnok F, Simon L , et al. A comparative dynamic
J Clin Gustrornterol, Vol. 12, N o . 3, 1990
270
F . M . MOSES ET AL.
study of the effectiveness of gastric cytoprotection by vitamin A , de-nol, sucralfate and ulcer healing by pirenzepine in patients with chronic gastric ulcer (a multiclinical and randomized study). Acta Physiol Hung 1984;64:379-84. Javor T, Bata M, Lovasz L , et al. Gastric cytoprotective effects of vitamin A and other carotenoids. Znt J Tissue React 1983;5:289-96. Mozsik G , Javor T, Toth Gy, Zsoldos T , Tigyi A . Interrelationships between the gastric cytoprotective effects of vitamin A and beta carotene and the gastric mucosal superoxide dismutase activity in rats. Acta Physiol Hung 1984;64:315-8. Javor T, Tarnok F , Past T, Nagy S. Cytoprotective effect of free radical scavengers against mucosal damage produced by different antirheumatic drugs. Int J Tissue React 1986;8:3540. Mozsik G, Bata M, Fiegler M, et al. Interrelationships between the membrane-bound ATP-dependent energy systems of the gastric mucosa and the gastric cytoprotective effect of beta carotene on the development of gastric muco-
J Clin Gastroenterol, Vol. 12, No. 3, 1990
10.
11.
12.
13.
14.
15.
sal damage produced by 0.6 M HCI in rats. Acta Physiol Hung 1984;64:301-7. Mahmood T, Tenenbaum S, Niu XT, Levenson SM, Seifter E, Demetriou AA. Prevention of duodenal ulcer formation in the rat by dietary vitamin A supplementation. J Parenter Enter Nutr 1986;10:747. Graham DY, Smith JL. Effects of aspirin and an aspirinacetaminophen combination on the gastric mucosa in normal subjects. Gastroenterology 1985;88:1922-5. Graham DY, Smith J L , Spjut HJ, Torres E. Gastric adaptation: studies in humans during continuous aspirin administration. Gastroenterology 1988;95:327-33. Rasche R, Butterfield WC. Vitamin A pretreatment of stress ulcers in rats. Arch Surg 1973;106:32&1. Holt KM, Hollander D. Acute gastric mucosal injury: pathogenesis and therapy. Annu Rev Med 1986;37:107-24. Laine L, Weinstein WM. Subepithelial hemorrhages and erosions of human stomach. Dig Dis Sci 1988;33:49&503.
