Peptic ulcer disease

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Peptic ulcers are thought to arise as a result of excessive amounts of gastric acid and pepsin or negligible mucosal resistance.14 It is logical, then, that any medication to combat the problem relates to the aforementioned factors and enhances the corresponding defense mechanism(s). Among the various categories of anti-ulcer drugs in the market, specific families contain aluminum. These include (a) anti-secretory medication and antacids and (b) mucosal protection agents.

A significant discovery in the treatment of peptic ulcers has emerged from advancements in the research of histamine H2-receptors and their antagonists. Akin to the H2-antagonists are antacids, which are well known to the majority of people suffering from ulcers and ulcer-related ailments. Antacids are recognized as agents capable of (a) managing acute and chronic gastroduodenal ulcerations15 and (b) contributing to ulcer healing.16

Mucosal protection agents act by increasing mucosal resistance or coating ulcer craters. Dominant among such agents is Sucralfate®. It is a complex of sulfated sucrose and Al(OH)3. The complex inhibits peptic hydrolysis. It also exhibits high affinity for ulcerated mucosal loci. Sucralfate® does not possess anti-secretory or acid-neutralizing activity. It acts by forming a larger complex with albumin, fibrinogen as well as other proteins. The arising species act as a barrier to acid, pepsin or bile acid intrusion, more like a molecular ulcer sealant

(bandage). To this end, pharmacologically, Sucralfate® has similar gastric and duodenal ulcer healing rates with the H2-antagonist Cimetidine®.17 The major advantage of Sucralfate®, however, over other anti-ulcer drugs is that it does not adsorb strongly to the ulcerated areas, thus avoiding potentially ensuing systemic side effects. The disadvantages of using Sucralfate® include constipation and a delay in voiding.

Do antacids possess ulcer-healing properties? What is the mechanism of their healing action? In fact, the actual mechanism of action is not known. The currently held view rides on the premise that the ulcer-healing action of antacids is primarily due to their neutralizing capacity of the luminal gastric acid. The case, though, may be more complex than that. To answer such a question one has to clarify the process of ulcer healing, which involves reconstruction of the mucosal architecture. The latter implies that the existing mucosal defect has to be restored through filling in the gap with proliferating epithelial and connective tissue cells. A number of growth factors participating actively in this process include the epidermal growth factor (EGF), its receptor EGF-R, Transforming growth factor (TGF^), basic fibroblast growth factor (bFGF) and others. EGF is an important growth factor, which (a) accelerates cell migration to achieve re-epithelialization of the ulcer base and (b) triggers cell proliferation and divisions, essential for filling ulcer craters, leading to reconstruction of epithelial structures within the ulcer scar.18 TGF^ is a growth factor, involved in signaling pathways supporting endothelial cell proliferation leading to ulcer healing. bFGF is a growth factor stimulating granulation tissue development and formation of microvessels through angiogenesis, thus contributing to ulcer healing and mucosal regeneration.19 Studies suggest that the pharmacological action of the medication emanates from activation of gastric mucosa genes encoding for EGF and EGF-R expression.20 EGF binds to EGF-R on the epithelial cell surface and activates a number of intracellular signaling pathways eventually leading to cell migration and proliferation. The latter process is crucial for filling in the injured ulcer locus (the ulcer crater). Concomitantly, the process of healing the ulcer scar is activated.

Consistent with the results of the aforementioned studies are studies conducted with antacids, like Talcid®, containing aluminum.21 Talcid® bears the active ingredient hydrotalcite, with the molecular formulation Mg6Al2(OH)10 CO34H2O. Hydrotalcite is characterized by a layered structure with the layers consisting of [Al(OH)2]+ and Mg(OH)2. In this layered structure (Figure 4.1), the aluminum ions bear positive charge. Water-bearing interlayers contain carbonate anions (CO32~), which provide the counteracting negative charge.

Collectively, cell migration, re-epithelialization and ultimate architectural restoration of the ulcer scar are the events contributing to ulcer healing. In this sense, the ulcer-healing process described above provides new insight into the molecular mechanism of action of pharmacological preparations in antacids, thus challenging the so far conventional belief on antacid healing action. Undoubtedly, the interaction of aluminum-containing antacids with the gastric

Figure 4.1 Molecular rendition of the hydrotalcite-layered structure, with positive charged layers composed of [Al(OH)2]+ ( ) and Mg(OH)2 (O), with a ratio of 1:3. The water-containing interlayers enclave carbonate anions neutralizing the positive charge

mucus is responsible for the activation of a cascade of (bio)chemical events, which most likely contribute to the protective function of antacids.

Equally appealing is the case of Helicobacter pylori, the bacterium causing chronic active gastritis and gastroduodenal ulcers.22 H. pylori can induce cellular damage to the gastric mucosa through cytotoxins (cytotoxin VacA) and enzymes23 that it excretes. This is accomplished by adhering to the surface epithelial cells, thus enabling the delivery of cytotoxins. The first such identified virulence factor, a cytotoxin (VacA), was termed 'vacuolating cytotoxin', due to its ability to generate vacuoles in eukaryotic cells and induce inflammatory response. The enzyme urease was also found to play an important role in the survival of the bacterium by degrading urea to ammonia, thus protecting the organism under extreme gastric pH conditions. Proteins (larger than 10 kDa) have been found to interfere with EGF binding to its receptor and EGF's stimulation of gastric cell proliferative responses. Other enzymes like lipase and proteases have also been found to be involved in the injury and creation of ulcerations, while factors like GroEL- and GroES-like heat-shock proteins (HSP) were found24 to help the bacterium tolerate extreme conditions (pH change). GroEL- and GroES-like HSP factors are chaperone proteins, belonging to the HSP family and contributing to the assembly or correct folding of target proteins by causing the target proteins to acquire or stabilize a specific conformation.

Employment of the Al(OH)3-containing hydrotalcite antacid (oral administration) was found to promote adsorption of all proteins secreted by H. pylori, including HSP, cytotoxin VacA and urease, and to counteract inhibition of EGF-stimulated cell proliferation. The latter is a very important process in ulcer healing. Moreover, the antacid Talcid® has been noted to induce mucosal activation of genes encoding for the EGF factor and its receptor EGF-R.25,26 Consequently, the aluminum-containing antacid removes factors which cause damage to the gastric epithelial cells (urease which generates ammonia and cytotoxins). Ultimately, the inhibition reversal of EGF-stimulated cell proliferation offers a new perspective in the pharmacological and mechanistic27 action of the drug and its clinical healing process.

On the basis of the aforementioned data, it appears that hydrotalcite can work efficiently toward healing of ulcerations due to bacterial as well as non-bacterial causes. Analogous studies conducted with other antacids, like Maalox® (Al(OH)3 and Mg(OH)2), emphasized the importance of the biochemical processes in the cytoprotection of gastric mucosa from H. py/ori and its pathogenicity on gastroduodenal ulcers. The results indicate that the antacid decreases H. py/ori HSP60 expression, thereby decreasing the inflammatory response in the gastric mucosa.28

The concurrent administration of aluminum pharmaceuticals with antibiotics is an issue of contemporary significance, as the interaction of both categories of agents results in variable activities.29 The underlying aluminum-antibiotic aqueous chemistry emerges as an important factor in the biological activity of the administered antacid and antibiotic drugs, often limiting the bioavailability of the antibiotic.30 Hence, concurrent use of both pharmaceuticals should proceed under strict medical supervision.

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