The Mode of Action of Sucralfate: The 1 x 1 x 1 Mechanism of Action S. SZABO Depts. of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
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Szabo S. The mode of action of sucralfate: the 1 x 1 Gastroenterol 1991, 26(suppl 18S), 7-12
X
1 mechanism of action. Scand J
Of the multiple actions of sucralfate, not all are equally relevant. In fact, certain actions of the drug contribute to healing of acute ulcers or to ulcer prevention, whereas other actions are more important in accelerating the healing of gastric and duodenal ulcers. The action of sucralfate can now be defined by the '1 X 1 X 1' mechanism of action-that is, one action of sucralfate is important for acute prevention, one is relevant to both acute and chronic protection, and one is important for chronic ulcer healing. Maintenance of mucosal vascular integrity and of blood flow, which ensures rapid epithelial restitution to repair superficial defects, are the most important acute actions of sucralfate. On the other hand, increased bicarbonate and mucus secretion seem to be relevant in both acute and chronic protection of the gastroduodenal mucosa. Finally, the enhanced binding by sucralfate of fibroblast growth factor and epidermal growth factor stimulates angiogenesis. granulation tissue, and epithelization for ulcer healing. This 1 X 1 X 1 theory of the mechanism of action of sucralfate concentrates on the relevant effects of this drug (which has more than a dozen actions) and may help to elucidate the molecular mechanism of action. Key words: Duodenal ulcer; gastroprotection; gastric ulcer; sucralfate
S. Szabo, M . D . . Ph. D . , Dept. of Pathology, Brigham and Women's Hospital, Boston, M A 02115. USA
Sucralfate is the only extensively used clinical drug, apart from colloidal bismuth subcitrate (CBS), which gives both acute gastroprotection and acceleration of chronic ulcer healing without a substantial decrease in gastric acidity. These acid-independent, acute and chronic actions of sucralfate are important in the light of the high incidence of ulcer recurrence after treatment with the H2-receptor antagonists. Although these antagonists have revolutionized the field of ulcer pharmacology by eliminating acute ulcers and accelerating ulcer healing, they have not markedly changed the natural history of ulcer disease. The problem is illustrated by the unusually high recurrence rates, which vary from 40% to 80% depending on clinical trials (l), and the small but real segment of the population who are non-responders to H2-receptor antagonists. Furthermore, one should remember that the
stomach is the only organ that is treated by suppression of its basic physiologic functionsecretion of acid and pepsin ( 2 ) . Thus, as with the disorders of other organs, such as the heart, kidney, and liver, it is more appropriate to treat diseases of the stomach and the duodenum without interfering with their basic physiologic functions. Although substantial advances have been made in understanding the mechanism of action of sucralfate, the mode of prevention of acute mucosal lesions and the acceleration of chronic ulcer healing remain incompletely understood. The critical evaluation of the mechanism of action of sucralfate in the 1990s is complicated by the fact that previous studies may need new interpretations. For example, the search for a single mechanism of action of sucralfate (such as receptor antagonism or inhibition of a well-defined
Scand J Gastroenterol Downloaded from informahealthcare.com by Queen's University on 04/21/13 For personal use only.
8
S. Szabo
enzyme) needs to be altered to look instead for a multiplicity of relevant actions (3). The interpretation of the apparent preferential binding of sucralfate and also of aluminium to gastric ulcers, as was first demonstrated in rats, has been confirmed but needs also to be modified (4). Although both sucralfate and aluminium preferentially cover the ulcer, this can happen to any compound that is picked up by the debris in a necrotic tissue. Furthermore, the binding does not provide a uniform coat, as was first imagined, but rather sucralfate provides a localized and uneven cover ( 5 ) . O n the other hand, the preferential binding of sucralfate to the ulcerated area as opposed to non-ulcerated gastric mucosa has been shown in patients (6). The benefits of coating probably needs reconsideration and may be interpreted as preferential binding by sucralfate of growth factors, such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). ACUTE VERSUS CHRONIC ACTIONS OF SUCRALFATE Numerous reviews exist on the pharmacologic spectrum of sucralfate and its mechanism of action (7, 8). My previous review was, however, probably the first to differentiate the single from multiple, and the acute from chronic actions of sucralfate (3). Although sucralfate exerts at least 10 actions on the gastrointestinal tract, not all of these are equally relevant to acute gastroprotection and chronic ulcer healing (3). For example, stimulation of cell proliferation is clearly important only for chronic ulcer healing. while the protection of the proliferative zone and vascular integrity are particularly important for acute gastroprotection (Fig. 1). In this review, additional information, clarifying the actions of sucralfate and their relevance to acute gastroprotection and to chronic ulcer healing, are given. It should be emphasized that acute actions mostly refer t o prevention of acute gastroduodenal lesions (Table I). This usually implies a single dose as a pretreatment in animal experiments, although a few similar results in clinical btudies are also available. In human studies, single
Table I. Acute and chronic actions of sucralfate Acute Prevention of acute gastroduodenal lesions Usually seen with pretreatment in animal experiments Seen with single or multiple treatments in human studies Chronic Healing of chronic ulcers After healing: maintenance therapy
or multiple treatments of short duration with drugs such as sucralfate are also generally labeled acute or subacute. O n the other hand, the chronic actions refer to healing of chronic gastric and duodenal ulcers, with special reference to maintenance therapy after the healing of the ulcer. The healing of chronic experimental ulcers can usually be investigated by use of acetic acid-induced chronic gastric ulcer or cystamine-produced chronic duodenal ulcers. Most of the data available at present are related to the acute actions of sucralfate, and we have very little, if any, evidence to explain its mode of action in accelerating healing or its efficacy in preventing relapse after the initial successful therapy. EFFECT OF SUCRALFATE O N ENDOGENOUS MEDIATORS Acute gastroprotection by sucralfate is influenced by endogenous mediators in the mucosa (Table 11). Hollander & Tarnawski (8) and Hollander et al. (9) initially described that, in rats, administration of sucralfate enhanced prostaglandin generation in the gastric mucosa. This observation was reproduced in several animal experiments but was not uniformly confirmed in human studies (10). Furthermore, the cyclooxygenase inhibitor
Table 11. Sucralfate and endogenous mediators Prostaglandins Increased in some animal experiments Increased in some human studies Sulfhydryls Implicated in some animal experiments Growth factors Animal and in vitro experiments show increased binding of EGF and bFGF
Mode of Action of Sucralfnte
9
-
PROTECTED
Maintenance
of blood flow
Scand J Gastroenterol Downloaded from informahealthcare.com by Queen's University on 04/21/13 For personal use only.
Restitution
NORMAL
3a
@surface
I
mucous cells ,Ils
endothelial cell DEEP DAMAGE
L
GRANULATION TTSSIJ E
HEALED
7
\
- -
Regeneration
Regeneration
Fig. 1. Normal, damaged, protected, and healed mucosa. Top. After pretreatment with a gastroprotective agent, such as sucralfate, the mucosal damage is limited to the superficial epithelium and does not involve the subepithelial capillaries. Bottom. After deep erosion and ulceration, cell regeneration (multiplication) involving angiogenesis and fibroblasts results in the production of granulation tissue. The healing is complete after the granulation tissue is covered by epithelium. (Reproduced with permission from Hollander D, Tarnawski A, eds. Gastric Cytoprotection. Plenum Press, 1989.)
indomethacin decreased the acute gastroprotection by sucralfate by only about so%,suggesting that about 50% of the action of sucralfate is not accounted for by increases in prostaglandin levels. Because of this interpretation, and because of the
discrepancies between the animal and human studies, it is probably fair to conclude that increased prostaglandin levels play some role but probably cannot explain all the acute protective actions of sucralfate.
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10
S. Szubo
Sulfhydryls (SH) were the second endogenous mediators implicated, and these have been investigated so far only in animal experiments (11). These studies showed that subcutaneous administration of the SH alkylator. N ethylmaleimide (NEM). abolished the gastroprotection induced by sucralfate. This action of endogenous SH-mediating gastroprotection is probably similar to the action of NEM in counteracting the gastroprotection by prostaglandins, polyamines, and other gastroprotective agents (12). Growth factors have also been implicated as mediators of sucralfate action. Nexe, Sr Poulsen found that sucralfate binds E G F in experimentally induced gastric and duodenal mucosal lesions (13). The action of growth factors is probably more relevant to the chronic action of sucralfate because they stimulate proliferation of cells. New studies (see below) strongly suggest that the enhanced binding of bFGF to sucralfate is particularly important in the healing of chronic ulcers because of the multiplicity of targets of FGF, which affects not only fibroblasts and endothelial cells. but also epithelial cells and smooth-muscle cells. Although EGF stimulates mostly epithelial cells and exerts only a slight effect on other cell components of granulation tissue, FGF 1s the most potent endogenous mitogen for endothelial cells, and for the regeneration of fibroblasts and other cells, including smooth muscle (14). Thus, growth factors might be the major mediators of the chronic actions of drugs such as sucralfate. Most recent data indicate that sucralfate might also release endogenous somatostatin (lS), which is both a gastroprotective agent and an inhibitor of gastric acid secretion. Further studies are needed to determine the possible contribution of somatostatin release under in vivo conditions to the gastroprotective and ulcer-healing properties of sucralfate. SUCRALFATE: T H E 1 X 1 x 1 MECHANISM OF ACTION Despite the multiplicity of actions of sucralfate, of which some might be more relevant for acute than chronic conditions. the 1 x 1 x 1 theory proposes that there is one action that probably explains the
acute gastroprotection by sucralfate, one action that is relevant to both acute and chronic protection, and one action of sucralfate that is related only to chronic ulcer healing (Table 111). Acute prevention: vascular integrity and restitution Prevention of early microvascular injury in the gastric mucosa (16), resulting in maintenance of blood flow (17), is essential for the energydependent, rapid epithelial restitution from the mucous neck cell (Fig. 1) (18). Data available in 1990 suggest that this is a key element in the acute gastroprotective actions of sucralfate (16-18). Pretreatment with sucralfate or its active components (sulfate or sucrose octasulfate (SOS)) prevents ethanol-induced microvascular endothelial injury in the gastric mucosa (as shown by the deposition of the vascular tracer monastral blue) (11). This morphologic demonstration of vascular injury is accompanied by functional maintenance of microcirculation, as is demonstrated by in vivo microscopy: the passage of erythrocytes in subepithelial capillaries is uninterrupted after the local administration of the water-soluble SOS component of sucralfate, while in non-pretreated animals the erythrocyte passage stops, invariably within 1 rnin after application of ethanol, HCI. or NaOH (Pihan and Szabo, unpublished observations). The migration of surface epithelial cells from the mucous neck, causing rapid restitution (18), is an energy-dependent process. It is clear that
Table 111. The 1 sucralfate
X
1
X
1 mechanism of action of
Acute prevention Prevention of vascular injury + Maintenance of blood flow + Rapid epithelial restitution from mucous neck cells Acute and chronic protection Increased bicarbonate and mucus secretion Dilution of endogenous and exogenous damaging agents Acid neutralization and pepsin exclusion Chronic ulcer healing 'Band-aid' theory: enhanced FGF and EGF binding + Angiogenesis -+ Granulation tissue -+ Epithelization
Mode of Action of Sucralfate
11
other hand, FGF is the most potent endothelial mitogen (19) that also stimulates granulation tissue formation and epithelization. Previous studies demonstrated an enhanced binding of EGF to sucralfate-treated ulcers (13). Recent studies showed strong and preferential binding of F G F to sucralfate and SOS (26). These Acute and chronicprotection: increased in vitro studies also demonstrated that the FGF bicarbonate and mucus secretion Increased bicarbonate and mucus secretion binding t o sucralfate and SOS was even more seems to be important in both acute gastroprotec- potent than that of heparin. and this strong tion and in acceleration of healing of chronic binding was acid-sensitive. The relevance of these gastric and duodenal ulcers, and probably even in in vitro binding studies of sucralfate to F G F might preventing ulcer relapse. For acute protection, correlate with in vivo animal experiments with because the major component of bicarbonate and the subcutaneously implanted sponge assay, in mucus is water (about 90%) and as histodilution which both sucralfate and its active component and intraluminal dilution of damaging agents is SOS stimulated angiogenesis, whereas it was one of the proposed mechanisms of acute gastro- mostly sucralfate and not SOS which enhanced protection (20-22), it is likely that enhanced the area of granulation tissue in the subcutaneous secretion and release of bicarbonate and mucus sponge in rats (27). I and my co-workers propose (26,27) that one may contribute to the delay in absorption and hence vascular contact with damaging agents (23). of the most relevant actions of sucralfate in its and also to intraluminal dilution of damaging acid-independent stimulation of chronic ulcer agents. It is probably not bicarbonate and mucus healing is the enhanced binding of FGF, E G F , per se that mediate gastroprotection, as most and possibly other growth factors that stimulate of the acute gastroprotection is a non-acid- granulation tissue formation, angiogenesis, and dependent phenomenon. O n the other hand, epithelization. These actions would explain the powerful ulcer healing actions of sucralfate withmucus might not only contribute to the mucusbicarbonate barrier but also provide protection out decreasing gastric acid concentration in the against one of the natural aggressors, such as stomach and the duodenum. pepsin (24, 25). Under chronic conditions, however, the REFERENCES neutralization of gastric acid by the secreted 1 . Marks IN, Samloff IM, eds. Sucralfate in peptic ulcer disease and gastritis: a worldwide view. Am J bicarbonate and the exclusion of the pepsin Med 1985, 79(suppl 2C), 1-64 by mucus could well be important elements con2. Szabo S. Bynum TE. Alternatives to the acidtributing to ulcer healing and prevention of ulcer oriented aooroach to ulcer disease: does ‘cvtooro.. , . tection’ exist in man? A new classification of antirelapse.
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maintenance of blood flow is a prerequisite for epithelial restitution, as recent pharmacologic studies have demonstrated that gastroprotective agents in vivo could not stimulate epithelial restitution directly (19).
Chronic ulcer healing: enhanced FGFand EGF binding The ‘band-aid theory of sucralfate action, as proposed more than 10 years ago, might be refined in the 1990s as being related to the preferential binding of FGF and E G F to sucralfate-treated ulcers. As discussed above, EGF stimulates mostly epithelial cell proliferation with very little effect, if any, on angiogenesis and other components of granulation tissue such as fibroblasts and monocytes (Fig. 1). O n the
ulcer agents. Scand J Gastroenterol 1988, 23, 1-6 Szabo S, Hollander D . Pathways of gastrointestinal protection and repair: mechanisms of action of sucralfate. Am J Med 1989, 86(suppl 6A), 2>31 Nagashima R, Hirano T. Selective binding of sucralfate to ulcer lesions. I. Experiments in rats with acetic acid-induced gastric ulcer receiving unlabelled sucralfate. Arzneimittelforsch 1980, 30, 80-83 Tarnawski A , Hollander D , Krause WJ, Zipser RD, Gergely H. Does sucralfateaffect the normal gastric mucosa? Histologic, ultrastructural and functional assessment. Gastroenterology 1986, 90, 893-905 Nakasano S, Nagashima R, Samloff M. Selective binding of sucralfate to gastric ulcer in man. Dig Dis Sci 1981, 26, 297-300
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7. Yamamoto E, Okabe S. Effects of sucralfate on Szabo S. Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by healing of chronic gastric ulcers in rats. In: Szabo S, Mozsik G. eds. New pharmacology of ulcer disease: 16,16-dimethyl prostaglandin Ez or sodium thiosulfate. Gastroenterology 1986, 91, 966-974 experimental and new therapeutic approaches. Elsevier. New York, 1987, 413-423 18. Lacey ER, Ito S. Rapid epithelial restitution in the 8. Hollander D. Tarnawski A. Protective effect of rat gastric mucosa after ethanol injury. Lab Invest sucralfate on the gastric mucosa mediated by en1984, 51, 573-583 dogenous prostaglandins. In: Szabo S, Mozsik G . 19. Feil W, Klimesch S, Karner P, et al. Importance of eds. New pharmacology of ulcer disease: experian alkaline microenvironment for rapid restitution of the rabbit duodenal mucosa in vitro. Gastromental and new therapeutic approaches. Elsevier, enterology 1989, 97, 112-122 New York. 1987. 404412 9. Hollander D. Tarnawski A. Gergely H. Zipser RD. 20. Dupuy D, Kronague JF, Jones AG, Szabo S. Gastric mucosal protection may be mediated Sucralfate protection of the gastric mucosa against ethanol-induced injury: a prostaglandin-mediated through increases in vascular permeability which create a histodilutional barrier. Gastroenterology process’?Scand J Gastroenterol1984,19(suppllOl). 97- 102 1988, 94, A615 10. Lam SK. Implications of sucralfate-induced ulcer 21. Palitzsch KD, Morales RE, Kronague JF, Szabo S. Biphasic effect of histamine on hemorrhagic healing and relapse. Am J Med 1989,86(suppl6A), 122- I26 mucosal lesions is related to vascular permeability: 11. Szabo S. Brown A . Prevention of ethanol-induced studies with histamine, H, , H2 and H,-antagonists vascular injury and gastric mucosal lesions by and bradykinin. Gastroenterology 1989, 96. A381 22. Robert A. Lancaster C, Gilbertson-Beadling S, sucralfate and its components: possible role of endogenous sulfhydryls. Proc SOCExp Biol Med Olafsson AS, Guth PH. Gastric adaptation to 1987. 185, 493-497 aspirin-induced gastric erosions in rats. Gastro12. Szabo S. Critical and timely review of the concept of enterology 1989, 96, A418 gastric cytoprotection. Acta Physiol Hung 1989.73. 23. Lippe IT, Szabo S. New mechanism of mucosal 115-127 protection: gastroprotective prostaglandin and sulfhydryls delay the absorption of ethanol and “‘C13. Ncxa E. Poulsen SS. Does epidermal growth factor aspirin from the rat stomach. Gastroenterology play a role in the action of sucralfate? Scand J Gastroenterol 1987. 22(suppl 127). 45-49 1990. 98. A79 24. Allen A. Garner A. Mucus and bicarbonate secre14. Folkman J . Klagsburn M. Angiogenic factors. tion in the stomach and their possible role in Science 1987, 235. 442-447 mucosal protection. Gut 1980, 21, 249-262 15. Yamada T. Boland CR. Cellular mechanisms of sucralfate and sucrose octasulphate (SOS) action. 25. Flemstrom G , Turnberg LA. Gastroduodenal defense mechanisms. Clin Gastroenterol 1984, 13, Proceedings of the 6th International Sucralfate Symposium. Gold Coast. Australia, August 19-21, 327-354 26. Folkman J , Szabo S, Shing Y.Sucralfate affinityfor 1990, 20 fibroblast growth factor. J Cell Biol1990.11 I , 223A 16. Szabo S, Trier JS, Brown A, Schnoor J . Early vascular injury and increased vascular permeability 27. Szabo S. Vattay P. Scarbrough E, Folkman J . Role of vascular factors, including angiogenesis in the in gastric mucosal injury caused by ethanol in the mechanism of action of sucralfate. Am J Med 1991 rat. Gastroenterology 1985. 88. 226236 (in press) 17. Pihan G , Majzoubi D, Haudenschild C, Trier JS.
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Szabo S. The mode of action of sucralfate: the 1 x 1 Gastroenterol 1991, 26(suppl 18S), 7-12
X
1 mechanism of action. Scand J
Of the multiple actions of sucralfate, not all are equally relevant. In fact, certain actions of the drug contribute to healing of acute ulcers or to ulcer prevention, whereas other actions are more important in accelerating the healing of gastric and duodenal ulcers. The action of sucralfate can now be defined by the '1 X 1 X 1' mechanism of action-that is, one action of sucralfate is important for acute prevention, one is relevant to both acute and chronic protection, and one is important for chronic ulcer healing. Maintenance of mucosal vascular integrity and of blood flow, which ensures rapid epithelial restitution to repair superficial defects, are the most important acute actions of sucralfate. On the other hand, increased bicarbonate and mucus secretion seem to be relevant in both acute and chronic protection of the gastroduodenal mucosa. Finally, the enhanced binding by sucralfate of fibroblast growth factor and epidermal growth factor stimulates angiogenesis. granulation tissue, and epithelization for ulcer healing. This 1 X 1 X 1 theory of the mechanism of action of sucralfate concentrates on the relevant effects of this drug (which has more than a dozen actions) and may help to elucidate the molecular mechanism of action. Key words: Duodenal ulcer; gastroprotection; gastric ulcer; sucralfate
S. Szabo, M . D . . Ph. D . , Dept. of Pathology, Brigham and Women's Hospital, Boston, M A 02115. USA
Sucralfate is the only extensively used clinical drug, apart from colloidal bismuth subcitrate (CBS), which gives both acute gastroprotection and acceleration of chronic ulcer healing without a substantial decrease in gastric acidity. These acid-independent, acute and chronic actions of sucralfate are important in the light of the high incidence of ulcer recurrence after treatment with the H2-receptor antagonists. Although these antagonists have revolutionized the field of ulcer pharmacology by eliminating acute ulcers and accelerating ulcer healing, they have not markedly changed the natural history of ulcer disease. The problem is illustrated by the unusually high recurrence rates, which vary from 40% to 80% depending on clinical trials (l), and the small but real segment of the population who are non-responders to H2-receptor antagonists. Furthermore, one should remember that the
stomach is the only organ that is treated by suppression of its basic physiologic functionsecretion of acid and pepsin ( 2 ) . Thus, as with the disorders of other organs, such as the heart, kidney, and liver, it is more appropriate to treat diseases of the stomach and the duodenum without interfering with their basic physiologic functions. Although substantial advances have been made in understanding the mechanism of action of sucralfate, the mode of prevention of acute mucosal lesions and the acceleration of chronic ulcer healing remain incompletely understood. The critical evaluation of the mechanism of action of sucralfate in the 1990s is complicated by the fact that previous studies may need new interpretations. For example, the search for a single mechanism of action of sucralfate (such as receptor antagonism or inhibition of a well-defined
Scand J Gastroenterol Downloaded from informahealthcare.com by Queen's University on 04/21/13 For personal use only.
8
S. Szabo
enzyme) needs to be altered to look instead for a multiplicity of relevant actions (3). The interpretation of the apparent preferential binding of sucralfate and also of aluminium to gastric ulcers, as was first demonstrated in rats, has been confirmed but needs also to be modified (4). Although both sucralfate and aluminium preferentially cover the ulcer, this can happen to any compound that is picked up by the debris in a necrotic tissue. Furthermore, the binding does not provide a uniform coat, as was first imagined, but rather sucralfate provides a localized and uneven cover ( 5 ) . O n the other hand, the preferential binding of sucralfate to the ulcerated area as opposed to non-ulcerated gastric mucosa has been shown in patients (6). The benefits of coating probably needs reconsideration and may be interpreted as preferential binding by sucralfate of growth factors, such as epidermal growth factor (EGF) and basic fibroblast growth factor (bFGF). ACUTE VERSUS CHRONIC ACTIONS OF SUCRALFATE Numerous reviews exist on the pharmacologic spectrum of sucralfate and its mechanism of action (7, 8). My previous review was, however, probably the first to differentiate the single from multiple, and the acute from chronic actions of sucralfate (3). Although sucralfate exerts at least 10 actions on the gastrointestinal tract, not all of these are equally relevant to acute gastroprotection and chronic ulcer healing (3). For example, stimulation of cell proliferation is clearly important only for chronic ulcer healing. while the protection of the proliferative zone and vascular integrity are particularly important for acute gastroprotection (Fig. 1). In this review, additional information, clarifying the actions of sucralfate and their relevance to acute gastroprotection and to chronic ulcer healing, are given. It should be emphasized that acute actions mostly refer t o prevention of acute gastroduodenal lesions (Table I). This usually implies a single dose as a pretreatment in animal experiments, although a few similar results in clinical btudies are also available. In human studies, single
Table I. Acute and chronic actions of sucralfate Acute Prevention of acute gastroduodenal lesions Usually seen with pretreatment in animal experiments Seen with single or multiple treatments in human studies Chronic Healing of chronic ulcers After healing: maintenance therapy
or multiple treatments of short duration with drugs such as sucralfate are also generally labeled acute or subacute. O n the other hand, the chronic actions refer to healing of chronic gastric and duodenal ulcers, with special reference to maintenance therapy after the healing of the ulcer. The healing of chronic experimental ulcers can usually be investigated by use of acetic acid-induced chronic gastric ulcer or cystamine-produced chronic duodenal ulcers. Most of the data available at present are related to the acute actions of sucralfate, and we have very little, if any, evidence to explain its mode of action in accelerating healing or its efficacy in preventing relapse after the initial successful therapy. EFFECT OF SUCRALFATE O N ENDOGENOUS MEDIATORS Acute gastroprotection by sucralfate is influenced by endogenous mediators in the mucosa (Table 11). Hollander & Tarnawski (8) and Hollander et al. (9) initially described that, in rats, administration of sucralfate enhanced prostaglandin generation in the gastric mucosa. This observation was reproduced in several animal experiments but was not uniformly confirmed in human studies (10). Furthermore, the cyclooxygenase inhibitor
Table 11. Sucralfate and endogenous mediators Prostaglandins Increased in some animal experiments Increased in some human studies Sulfhydryls Implicated in some animal experiments Growth factors Animal and in vitro experiments show increased binding of EGF and bFGF
Mode of Action of Sucralfnte
9
-
PROTECTED
Maintenance
of blood flow
Scand J Gastroenterol Downloaded from informahealthcare.com by Queen's University on 04/21/13 For personal use only.
Restitution
NORMAL
3a
@surface
I
mucous cells ,Ils
endothelial cell DEEP DAMAGE
L
GRANULATION TTSSIJ E
HEALED
7
\
- -
Regeneration
Regeneration
Fig. 1. Normal, damaged, protected, and healed mucosa. Top. After pretreatment with a gastroprotective agent, such as sucralfate, the mucosal damage is limited to the superficial epithelium and does not involve the subepithelial capillaries. Bottom. After deep erosion and ulceration, cell regeneration (multiplication) involving angiogenesis and fibroblasts results in the production of granulation tissue. The healing is complete after the granulation tissue is covered by epithelium. (Reproduced with permission from Hollander D, Tarnawski A, eds. Gastric Cytoprotection. Plenum Press, 1989.)
indomethacin decreased the acute gastroprotection by sucralfate by only about so%,suggesting that about 50% of the action of sucralfate is not accounted for by increases in prostaglandin levels. Because of this interpretation, and because of the
discrepancies between the animal and human studies, it is probably fair to conclude that increased prostaglandin levels play some role but probably cannot explain all the acute protective actions of sucralfate.
Scand J Gastroenterol Downloaded from informahealthcare.com by Queen's University on 04/21/13 For personal use only.
10
S. Szubo
Sulfhydryls (SH) were the second endogenous mediators implicated, and these have been investigated so far only in animal experiments (11). These studies showed that subcutaneous administration of the SH alkylator. N ethylmaleimide (NEM). abolished the gastroprotection induced by sucralfate. This action of endogenous SH-mediating gastroprotection is probably similar to the action of NEM in counteracting the gastroprotection by prostaglandins, polyamines, and other gastroprotective agents (12). Growth factors have also been implicated as mediators of sucralfate action. Nexe, Sr Poulsen found that sucralfate binds E G F in experimentally induced gastric and duodenal mucosal lesions (13). The action of growth factors is probably more relevant to the chronic action of sucralfate because they stimulate proliferation of cells. New studies (see below) strongly suggest that the enhanced binding of bFGF to sucralfate is particularly important in the healing of chronic ulcers because of the multiplicity of targets of FGF, which affects not only fibroblasts and endothelial cells. but also epithelial cells and smooth-muscle cells. Although EGF stimulates mostly epithelial cells and exerts only a slight effect on other cell components of granulation tissue, FGF 1s the most potent endogenous mitogen for endothelial cells, and for the regeneration of fibroblasts and other cells, including smooth muscle (14). Thus, growth factors might be the major mediators of the chronic actions of drugs such as sucralfate. Most recent data indicate that sucralfate might also release endogenous somatostatin (lS), which is both a gastroprotective agent and an inhibitor of gastric acid secretion. Further studies are needed to determine the possible contribution of somatostatin release under in vivo conditions to the gastroprotective and ulcer-healing properties of sucralfate. SUCRALFATE: T H E 1 X 1 x 1 MECHANISM OF ACTION Despite the multiplicity of actions of sucralfate, of which some might be more relevant for acute than chronic conditions. the 1 x 1 x 1 theory proposes that there is one action that probably explains the
acute gastroprotection by sucralfate, one action that is relevant to both acute and chronic protection, and one action of sucralfate that is related only to chronic ulcer healing (Table 111). Acute prevention: vascular integrity and restitution Prevention of early microvascular injury in the gastric mucosa (16), resulting in maintenance of blood flow (17), is essential for the energydependent, rapid epithelial restitution from the mucous neck cell (Fig. 1) (18). Data available in 1990 suggest that this is a key element in the acute gastroprotective actions of sucralfate (16-18). Pretreatment with sucralfate or its active components (sulfate or sucrose octasulfate (SOS)) prevents ethanol-induced microvascular endothelial injury in the gastric mucosa (as shown by the deposition of the vascular tracer monastral blue) (11). This morphologic demonstration of vascular injury is accompanied by functional maintenance of microcirculation, as is demonstrated by in vivo microscopy: the passage of erythrocytes in subepithelial capillaries is uninterrupted after the local administration of the water-soluble SOS component of sucralfate, while in non-pretreated animals the erythrocyte passage stops, invariably within 1 rnin after application of ethanol, HCI. or NaOH (Pihan and Szabo, unpublished observations). The migration of surface epithelial cells from the mucous neck, causing rapid restitution (18), is an energy-dependent process. It is clear that
Table 111. The 1 sucralfate
X
1
X
1 mechanism of action of
Acute prevention Prevention of vascular injury + Maintenance of blood flow + Rapid epithelial restitution from mucous neck cells Acute and chronic protection Increased bicarbonate and mucus secretion Dilution of endogenous and exogenous damaging agents Acid neutralization and pepsin exclusion Chronic ulcer healing 'Band-aid' theory: enhanced FGF and EGF binding + Angiogenesis -+ Granulation tissue -+ Epithelization
Mode of Action of Sucralfate
11
other hand, FGF is the most potent endothelial mitogen (19) that also stimulates granulation tissue formation and epithelization. Previous studies demonstrated an enhanced binding of EGF to sucralfate-treated ulcers (13). Recent studies showed strong and preferential binding of F G F to sucralfate and SOS (26). These Acute and chronicprotection: increased in vitro studies also demonstrated that the FGF bicarbonate and mucus secretion Increased bicarbonate and mucus secretion binding t o sucralfate and SOS was even more seems to be important in both acute gastroprotec- potent than that of heparin. and this strong tion and in acceleration of healing of chronic binding was acid-sensitive. The relevance of these gastric and duodenal ulcers, and probably even in in vitro binding studies of sucralfate to F G F might preventing ulcer relapse. For acute protection, correlate with in vivo animal experiments with because the major component of bicarbonate and the subcutaneously implanted sponge assay, in mucus is water (about 90%) and as histodilution which both sucralfate and its active component and intraluminal dilution of damaging agents is SOS stimulated angiogenesis, whereas it was one of the proposed mechanisms of acute gastro- mostly sucralfate and not SOS which enhanced protection (20-22), it is likely that enhanced the area of granulation tissue in the subcutaneous secretion and release of bicarbonate and mucus sponge in rats (27). I and my co-workers propose (26,27) that one may contribute to the delay in absorption and hence vascular contact with damaging agents (23). of the most relevant actions of sucralfate in its and also to intraluminal dilution of damaging acid-independent stimulation of chronic ulcer agents. It is probably not bicarbonate and mucus healing is the enhanced binding of FGF, E G F , per se that mediate gastroprotection, as most and possibly other growth factors that stimulate of the acute gastroprotection is a non-acid- granulation tissue formation, angiogenesis, and dependent phenomenon. O n the other hand, epithelization. These actions would explain the powerful ulcer healing actions of sucralfate withmucus might not only contribute to the mucusbicarbonate barrier but also provide protection out decreasing gastric acid concentration in the against one of the natural aggressors, such as stomach and the duodenum. pepsin (24, 25). Under chronic conditions, however, the REFERENCES neutralization of gastric acid by the secreted 1 . Marks IN, Samloff IM, eds. Sucralfate in peptic ulcer disease and gastritis: a worldwide view. Am J bicarbonate and the exclusion of the pepsin Med 1985, 79(suppl 2C), 1-64 by mucus could well be important elements con2. Szabo S. Bynum TE. Alternatives to the acidtributing to ulcer healing and prevention of ulcer oriented aooroach to ulcer disease: does ‘cvtooro.. , . tection’ exist in man? A new classification of antirelapse.
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maintenance of blood flow is a prerequisite for epithelial restitution, as recent pharmacologic studies have demonstrated that gastroprotective agents in vivo could not stimulate epithelial restitution directly (19).
Chronic ulcer healing: enhanced FGFand EGF binding The ‘band-aid theory of sucralfate action, as proposed more than 10 years ago, might be refined in the 1990s as being related to the preferential binding of FGF and E G F to sucralfate-treated ulcers. As discussed above, EGF stimulates mostly epithelial cell proliferation with very little effect, if any, on angiogenesis and other components of granulation tissue such as fibroblasts and monocytes (Fig. 1). O n the
ulcer agents. Scand J Gastroenterol 1988, 23, 1-6 Szabo S, Hollander D . Pathways of gastrointestinal protection and repair: mechanisms of action of sucralfate. Am J Med 1989, 86(suppl 6A), 2>31 Nagashima R, Hirano T. Selective binding of sucralfate to ulcer lesions. I. Experiments in rats with acetic acid-induced gastric ulcer receiving unlabelled sucralfate. Arzneimittelforsch 1980, 30, 80-83 Tarnawski A , Hollander D , Krause WJ, Zipser RD, Gergely H. Does sucralfateaffect the normal gastric mucosa? Histologic, ultrastructural and functional assessment. Gastroenterology 1986, 90, 893-905 Nakasano S, Nagashima R, Samloff M. Selective binding of sucralfate to gastric ulcer in man. Dig Dis Sci 1981, 26, 297-300
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S. Szabo
7. Yamamoto E, Okabe S. Effects of sucralfate on Szabo S. Early microcirculatory stasis in acute gastric mucosal injury in the rat and prevention by healing of chronic gastric ulcers in rats. In: Szabo S, Mozsik G. eds. New pharmacology of ulcer disease: 16,16-dimethyl prostaglandin Ez or sodium thiosulfate. Gastroenterology 1986, 91, 966-974 experimental and new therapeutic approaches. Elsevier. New York, 1987, 413-423 18. Lacey ER, Ito S. Rapid epithelial restitution in the 8. Hollander D. Tarnawski A. Protective effect of rat gastric mucosa after ethanol injury. Lab Invest sucralfate on the gastric mucosa mediated by en1984, 51, 573-583 dogenous prostaglandins. In: Szabo S, Mozsik G . 19. Feil W, Klimesch S, Karner P, et al. Importance of eds. New pharmacology of ulcer disease: experian alkaline microenvironment for rapid restitution of the rabbit duodenal mucosa in vitro. Gastromental and new therapeutic approaches. Elsevier, enterology 1989, 97, 112-122 New York. 1987. 404412 9. Hollander D. Tarnawski A. Gergely H. Zipser RD. 20. Dupuy D, Kronague JF, Jones AG, Szabo S. Gastric mucosal protection may be mediated Sucralfate protection of the gastric mucosa against ethanol-induced injury: a prostaglandin-mediated through increases in vascular permeability which create a histodilutional barrier. Gastroenterology process’?Scand J Gastroenterol1984,19(suppllOl). 97- 102 1988, 94, A615 10. Lam SK. Implications of sucralfate-induced ulcer 21. Palitzsch KD, Morales RE, Kronague JF, Szabo S. Biphasic effect of histamine on hemorrhagic healing and relapse. Am J Med 1989,86(suppl6A), 122- I26 mucosal lesions is related to vascular permeability: 11. Szabo S. Brown A . Prevention of ethanol-induced studies with histamine, H, , H2 and H,-antagonists vascular injury and gastric mucosal lesions by and bradykinin. Gastroenterology 1989, 96. A381 22. Robert A. Lancaster C, Gilbertson-Beadling S, sucralfate and its components: possible role of endogenous sulfhydryls. Proc SOCExp Biol Med Olafsson AS, Guth PH. Gastric adaptation to 1987. 185, 493-497 aspirin-induced gastric erosions in rats. Gastro12. Szabo S. Critical and timely review of the concept of enterology 1989, 96, A418 gastric cytoprotection. Acta Physiol Hung 1989.73. 23. Lippe IT, Szabo S. New mechanism of mucosal 115-127 protection: gastroprotective prostaglandin and sulfhydryls delay the absorption of ethanol and “‘C13. Ncxa E. Poulsen SS. Does epidermal growth factor aspirin from the rat stomach. Gastroenterology play a role in the action of sucralfate? Scand J Gastroenterol 1987. 22(suppl 127). 45-49 1990. 98. A79 24. Allen A. Garner A. Mucus and bicarbonate secre14. Folkman J . Klagsburn M. Angiogenic factors. tion in the stomach and their possible role in Science 1987, 235. 442-447 mucosal protection. Gut 1980, 21, 249-262 15. Yamada T. Boland CR. Cellular mechanisms of sucralfate and sucrose octasulphate (SOS) action. 25. Flemstrom G , Turnberg LA. Gastroduodenal defense mechanisms. Clin Gastroenterol 1984, 13, Proceedings of the 6th International Sucralfate Symposium. Gold Coast. Australia, August 19-21, 327-354 26. Folkman J , Szabo S, Shing Y.Sucralfate affinityfor 1990, 20 fibroblast growth factor. J Cell Biol1990.11 I , 223A 16. Szabo S, Trier JS, Brown A, Schnoor J . Early vascular injury and increased vascular permeability 27. Szabo S. Vattay P. Scarbrough E, Folkman J . Role of vascular factors, including angiogenesis in the in gastric mucosal injury caused by ethanol in the mechanism of action of sucralfate. Am J Med 1991 rat. Gastroenterology 1985. 88. 226236 (in press) 17. Pihan G , Majzoubi D, Haudenschild C, Trier JS.
