An estimated 4 million people worldwide suffer from gastric ulcers each year, a serious gastrointestinal condition that has a substantial negative impact on health [1]. In the general population, its lifetime prevalence is expected to be between 5 and 10% [2]. About 6000 individuals pass away from the disease's consequences, and 40,000 people get surgery to relieve their chronic symptoms [3]. It is a serious gastrointestinal condition that significantly impairs quality of life and places a heavy burden on communities and healthcare systems [4].

A rupture in the stomach lining's mucosa that extends more than 5 mm in diameter and passes through the muscularis mucosa is known as a gastric ulcer. Changes in the stomach's defensive mechanisms can lead to changes in the gastric mucosa, which can ultimately induce erosion and ulceration [5]. The aetiology of stomach ulcers has also been linked to Helicobacter pylori infection, the use of non-steroidal anti-inflammatory medicines (NSAIDs), and environmental and behavioural variables such as stress, alcohol, poor diet, and smoking [6]. Among these, Helicobacter pylori (H. pylori) infections and long-term use of nonsteroidal anti-inflammatory medicines (NSAIDs) are the two main harmful causes linked to gastric ulcers and ulcer recurrence [7].

Over the course of a patient's lifetime, gastric ulcers might heal and reappear in the same spot or somewhere else. Its development is essentially caused by an imbalance in the luminal surface of the stomach mucosa between harmful agents like acid and pepsin and mucosal defensive mechanisms like mucus, bicarbonate, prostaglandins (PGs), and mucosal blood flow [7]. Abdominal pain and discomfort are signs of gastric ulcers. Weight loss, decreased appetite, bloating, nausea, and vomiting are further symptoms. Some people may vomit, have blood in their stools, or have black faeces, which are signs of gastrointestinal bleeding [8]. Many contemporary antiulcer medications, such as H2-blockers and M1-blockers, have been created; nevertheless, these medications are linked to the risk of drug interaction, side effects, and a higher rate of relapses during ulcer therapy. It is necessary to look for novel antiulcer medications, especially those derived from plants, in order to improve protection and reduce toxicity [9]. The two most popular treatments for peptic ulcers, histamine-2 (H2) receptor antagonists and proton pump inhibitors (PPIs), have shown several drug interactions, adverse side effects, and relapses.

The Importance of the Study

Gastric ulcers are a common gastrointestinal disorder with significant public health implications, including increased healthcare costs, decreased productivity, recurrence, gastric bleeding, perforations, and cancer risk. It is important to conduct a study on the condition. The public will receive vital information from this study in order to enhance digestive health, early intervention, and lessen misconceptions. The public has little knowledge about the effects of Helicobacter pylori and the use of NSAIDs, and there is much contradictory and false information about stomach ulcer illness, such as attributing the condition only to hunger, spicy meals, stress, and other aggravating causes. Antacids and other antiulcer medications are now more frequently prescribed over-the-counter as a result of this, which have been consistently linked to serious side effects. The public is becoming increasingly aware of problems with over-prescription, antibiotic misuse, and an increase in antimicrobial resistance being investigated for several disorders.

Concept of Gastric Ulcer

The word "ulcer" was derived from the French word "ulcere" and the Latin word "ulcus," meaning a sore, sore spot, or painful spot (ca. 1400 CE). Generally, an ulcer is an area of erosion, disintegration, and necrosis of epithelial tissue of the skin or mucous membrane. The peptic ulcer is classified into gastric ulcer (stomach), oesophageal ulcer (oesophagus), and duodenal ulcer (duodenum), based on anatomical location [10]. A gastric ulcer could be defined as a break in the mucosa of the stomach lining that penetrates through the muscularis mucosa and extends more than 5 mm in diameter [5]. The main focus of this research is on gastric ulcers, which are statistically increasing due to several factors.

Ulcer Prevalence

According to Xie et al. [11], a systematic review of the global, regional, and national burden of peptic ulcer disease, PUD affected approximately 8.09 million people worldwide in 2019, with a global incidence of 3.59 million, an age-standardized prevalence rate of 99.4/100,000 population, and a mortality rate of 3.0. South Asia had the greatest age-standardized prevalence rate (156.6/100,000), while Latin America and the Caribbean had the lowest (41.8/100,000). Despite high rates of Helicobacter pylori infection, peptic ulcers were previously thought to be uncommon in Africans. However, this was due to a lack of diagnostic facilities, and prospective endoscopic surveys revealed that ulcers were as common in Africa as in many other countries, although there is a significant variation in prevalence within countries and across the continent [12]. Although the exact frequency of peptic ulcer illness in Nigerians is unknown, autopsy research conducted in Ibadan found a 5% prevalence rate [13]. In Nigeria's northern Savannah, there was a noticeable shift in the prevalence and pattern of ulcers; patients were primarily older and male, and gastric ulcers were more common than duodenal ulcers [12].

Figure 1: The Stomach's Anatomy [14].

The stomach is located in the upper part of the abdomen, directly beneath the diaphragm. The cardia, fundus, body, and pyloric portion are the four main parts of the stomach. The oesophagal aperture into the stomach is surrounded by the cardia. The fundus is the circular area to the left and above the cardia. The big core part of the stomach, the body, is inferior to the fundus. There are three distinct sections within the pyloric portion. The pyloric antrum, the initial area, joins the stomach's body. The pyloric canal, the second region, connects to the duodenum by the pylorus, the third region. When the stomach is empty, the mucosa is visible to the unassisted eye in huge folds called rugae. A smooth muscle sphincter known as the pyloric sphincter (valve) connects the pylorus to the duodenum of the small intestine. The stomach's convex lateral border is referred to as the greater curvature, while its concave medial border is known as the lesser curvature [14].

Figure 2: Stomach Histology [14].

Surface mucous cells are a type of simple columnar epithelial cell that covers the mucosa's surface. Gastric pits are a type of lamina propria (areolar) found in the mucosa. Each gastric pit receives secretions from many gastric glands, which subsequently enter the stomach lumen. Mucous neck cells, chief cells, and parietal cells are the three types of exocrine gland cells found in the gastric glands that discharge their products into the stomach lumen. Mucus is secreted by mucous neck cells as well as surface mucous cells. Hydrochloric acid and intrinsic factor, which are required for the absorption of vitamin B12, are produced by parietal cells. Pepsinogen and gastric lipase are secreted by the main (zymogenic) cells. Gastric secretions are produced by the mucous, parietal, and main cells.

Gastric glands also contain the G cell, a kind of enteroendocrine cell that secretes the hormone gastrin into the circulation and is primarily found in the pyloric antrum. Numerous aspects of stomach activity are stimulated by this hormone. Deep under the mucosa are three further layers. Areolar connective tissue makes up the stomach's submucosa. Three layers of smooth muscle make up the muscularis: an inner oblique layer, a middle circular layer, and an exterior longitudinal layer. The oblique layer is mostly restricted to the stomach's body. Simple squamous epithelium (mesothelium) and areolar connective tissue make up the serosa; the region of the serosa that covers the stomach is a part of the visceral peritoneum. The visceral peritoneum, also known as the lesser omentum, rises to the liver at the stomach's lesser curvature. The visceral peritoneum descends as the greater omentum at the stomach's greater curvature and covers the intestines [14].

Etiology

Ulcers are caused by a variety of factors. At least eight risk variables, including stress, NSAID use, H. pylori infection, smoking, and alcohol consumption, have been identified as contributing to the aetiology of ulcers.

HELICOBACTER PYLORI: Two Australian scientists, J. Robin Warren and Barry J. Marshall, identified Helicobacter pylori as a cause of ulcers in 1982. [2]. Epidemiological studies have shown a substantial correlation between H. pylori infection and gastroduodenal ulcers. Over 50% of people worldwide suffer from a persistent stomach mucosal H. pylori infection. Srikanta et al. [10], H. pylori is an etiologic factor for the majority of gastric ulcer sufferers and may raise a person's risk of stomach cancer. Although the precise method of H. pylori transmission is uncertain, it seems to be a faecal-oral route of person-to-person transmission [15]. H. pylori colonises the human stomach.

NSAID: A coating of mucus that is secreted by certain prostaglandins shields the stomach mucosa from gastric acid. NSAIDs prevent cyclooxygenase-1 from doing its job, which is necessary for prostaglandin synthesis [3]. NSAIDs block cyclooxygenase, deplete endogenous prostaglandins, and directly harm the stomach's mucosal defences [16]. Diclofenac and aspirin are the most frequently used NSAID medications [17]. While non-aspirin NSAID use raises the risk of stomach ulcers to varying degrees in people over 55, depending on race and ulcer history, aspirin increases the risk of gastric ulcers in individuals of all ages [18].

ACID AND PEPSIN: Strong digestive juices are thought to play a role in ulcer development. There are various ways that the stomach can defend itself against these liquids. These are created as mucus that covers and protects stomach tissue, like a lubricant. They create bicarbonate, which neutralises and converts digestive juices into less toxic compounds [3].

STRESS: One well-known cause of stomach ulcers, often known as stress ulcers, is stress brought on by major health issues, such as those requiring treatment in an intensive care unit. [19]. Although ulcers were originally thought to be primarily caused by persistent life stress, this is no longer the case. However, it is still sometimes thought to be involved [20]. People undergoing major surgery and those with serious burns are two examples of physical stress that can result in ulcers [21].

ALCOHOL: Drinking alcohol increases the risk. By blocking COX-1 receptor enzymes, chronic alcohol consumption disrupts the stomach mucosal barrier and lowers the synthesis of cytoprotective prostaglandin [22]. Although alcohol has been shown to damage animals' gastrointestinal mucosa, the use of 100% methanol seems to be linked to this damage. Due to its lipid solubility, pure ethanol clearly and immediately damages the mucosa. Since most people do not take absolute ethanol, it is doubtful that mucosal injury occurs at ethanol concentrations lower than 10%. However, higher concentrations of ethanol decrease acid secretion, whereas lower concentrations (5%) may somewhat increase the release of gastric acid. This is physically fascinating, but it has little bearing on how ulcers arise or are treated [23].

SMOKING: Smoking increases the risk of developing a stomach ulcer. According to Mal Chow et al. [24], smoking cigarettes reduces circulating epidermal growth factor and increases the formation of free radicals in the stomach mucosa. Smoking and the development of ulcers have been linked in certain studies. Others who have examined the dangers in further detail have discovered that smoking may not be a significant risk factor on its own unless it is linked to an H. pylori infection [25].

GENETICS: Gastric ulcers are significantly influenced by genetics. Although there is no genetic link to H. pylori infection, a family history of gastric ulcer disease is a risk factor since certain genetic characteristics predispose to the disease [26]. According to certain research findings, stomach body ulcers and genetic variation at the PGR-RFLP gene locus are significantly correlated [27].

ZOLLINGER-ELLISON SYNDROME: This disorder is brought on by a tumour that secretes gastrin, which results in an excess of gastric acid and ulcer disease. The most prevalent symptoms are gastro-oesophageal reflux disease, diarrhoea, and abdominal pain. Weight loss, gastrointestinal haemorrhage, nausea, and vomiting are less frequent manifestations [28].

Gastric Ulcer Pathogenesis

Since the pathogenic variables determine the pathophysiology of stomach ulcers, the pathogenesis determines the therapy options. For instance, the first line of treatment for Helicobacter pylori-induced stomach ulcers is antibiotics. On the other hand, medications that neutralise luminal acidity and restrict stomach acid secretion are frequently used to treat NSAID-mediated gastric mucosal damage, thereby preventing gastric ulcers [29].

Figure 3: Pathogenesis of Gastric Ulcer [30].

Gastric Ulcer Caused By NSAIDs

"Non-Steroidal Anti-Inflammatory Drugs" is what NSAID stands for. These drugs are used to treat fever, pain, and other inflammatory conditions [31]. They have been approved by the Food and Drug Administration (FDA) for use as anti-inflammatory, analgesic, and antipyretic medications [32].

Every day, around 30 million people take nonsteroidal anti-inflammatory medicines (NSAIDs) [33]. Among all drugs, these are some of the most commonly taken and abused [34]. NSAIDs are the main treatment for pain and inflammation. These medications treat acute inflammatory problems like sports injuries, fractures, sprains, acute arthritic symptoms, and other soft tissue injuries, as well as chronic joint diseases like rheumatoid arthritis. Additionally, they alleviate headache and migraine pain as well as menstrual, dental, and post-operative pain [35]. The majority of NSAIDs are sold over the counter and come in a variety of forms, including as tablets, injections, and gels. There are currently around fifty different NSAIDs available worldwide.

Although the precise number of NSAID-related hospital admissions and fatalities in Nigeria is unknown, the medications' widespread use indicates that side effects are unavoidable. The most commonly given NSAID is aspirin [36]. In the US, NSAID use is thought to be responsible for 76,000 hospital admissions and 7,600 fatalities [37]. NSAID-related ulcers and gastrointestinal bleeding are the main causes of these hospital stays and fatalities. According to McCarthy et al. [38], 20–30% of long-term NSAID users had peptic ulcers, with gastric ulcers occurring almost six times more frequently than duodenal ulcers. Aspirin, Diclofenac, Indomethacin, Ibuprofen, Naproxen, Piroxicam, Nabumetone, and Celecoxib are a few examples of NSAIDs.

Mechanism of Action of NSAIDs

NSAIDs work by inhibiting the cyclooxygenase (COX) enzyme, which is involved in the production of prostaglandins (PGs) and thromboxane (TX) [39].

Figure 4: Inhibition of the Cyclooxygenase Enzyme [40].

Aspirin

Aspirin, also known as acetylsalicylic acid, has been used since the late 1800s and is one of the most widely used NSAIDs. The cyclooxygenase (COX) enzymes that carry out the body's prostaglandin synthesis are blocked by aspirin and other NSAIDs. The enzyme comes in two forms: COX-1, which is responsible for the normal physiological production of prostaglandins, and COX-2, which mediates the body's response to arthritis and other inflammatory conditions. Sadly, aspirin, ibuprofen, and other NSAIDs block both COX-1 and COX-2 enzymes, which prevents the body from responding to inflammation as well as several protective functions, such as the regulation of stomach acid production.

By acetylating Ser-530 in COX-1 and Ser-516 in COX-2, aspirin covalently alters COX enzymes, making them irreversibly inactive [41]. When it comes to converting arachidonic acid into prostaglandins, aspirin can permanently inactivate COX-1 by covalently acetylating a serine residue. But there is a significant difference between aspirin's interaction with COX-2 and COX-1. Aspirin still inhibits prostaglandin synthesis and covalently acetylates a serine residue in COX-2, but the acetylated COX-2 can still convert arachidonic acid to 15-R-hydroxyepitetraenoic acid. 5-lipoxygenase can subsequently convert this material to 15-epi-(R)-lipoxin A4, which is also known as "aspirin-triggered lipoxin" [42]. Similar to its epimer, lipoxin A4 (LXA4), this lipoxin has numerous anti-inflammatory properties [43]. Interestingly, it is also a highly effective endogenous gastroprotective agent [44].

The Cyclooxygenase (Cox) Pathway

The substrate for the Cyclooxygenase (COX) pathway is "arachidonic acid," a polyunsaturated fatty acid with 20 carbons that is present in the membranes of the majority of bodily tissues. It makes up 5 to 15% of the fatty acids in phospholipids and is found in cell membranes. Eicosanoids are paracrine hormones that operate near the site of synthesis rather than travelling via blood to distant places. All eicosanoids are generated from arachidonic acid. Prostaglandins, thromboxane, and leukotrienes are the three classes of eicosanoids. First identified in prostate glands, prostaglandins mediate pain, inflammation, and fever; platelets create thromboxane, which aids in clotting; and leukotrienes, initially identified in leucocytes, mediate inflammation and anaphylaxis.

COX-1: Constitutively expressed, this enzyme catalyses the synthesis of mediators from arachidonic acid, such as prostaglandin and thromboxane. A significant part in numerous physiological processes, such as the protection of the stomach mucosa. Some NSAID-related adverse effects, such as gastritis and PUD, are caused by the relatively unintentional suppression of this mechanism.

COX-2: Inflammation-induced expression. catalyzes the conversion of arachidonic acid into inflammatory prostaglandins and other mediators. NSAIDs provide the intended symptomatic relief by inhibiting the effects of these prostaglandins, which are involved in inflammation, pain, and fever. Arachidonic acid is converted into prostanoids, a class of lipid signalling molecules that includes prostaglandins (PGs) and thromboxanes (TXs), by this family of isoenzymes. Arachidonic acid is oxygenated by the COX isoenzymes to produce PGG2, which is the precursor to all other prostanoids. Because of this, prostaglandin G/H synthases (PTGSs) are another name for COX isoenzymes.

Gene Expression of COX 1 AND 2

In the majority of tissues where it is present, COX-1 is constitutively expressed and extensively dispersed. The 2.8 kb mRNA produced by its gene, ptgs-1, is comparatively stable. In contrast, the 4 kb COX-2 mRNA turns over quickly because of instability sequences in the 3'-untranslated region of the COX-2 gene, ptgs-2, which is an immediate early gene that is activated by a wide range of inflammatory and proliferative stimuli [45,46]. The two COX isoforms are clearly explained by the difference in the pattern of gene expression, which suggests that COX-1 produces prostaglandins necessary for homeostatic processes, such as gastric cytoprotection and hemostasis, while COX-2 is primarily involved in prostaglandin formation during pathophysiologic states, such as inflammation and tumorigenesis. Compared to constitutively produced COX-1, COX-2 has a shorter half-life of less than 3.5 hours, while COX-1 mRNA has a half-life of roughly 12 to 15 hours [47]. This suggests a close temporal relationship between tissue injury, COX-2 expression, and high PGE2. Increased prostaglandin E2 at the site of injury, the start of pain, and the analgesic effects of both non-selective NSAIDs and selective COX-2 inhibitors may all be influenced by elevated COX-2 following tissue damage [48]. Increased COX-1 is essential for the production of prostaglandin, which protects the mucosa. The majority of cells and organs, including the stomach, platelets, endothelial cells, and the kidney, constitutively express COX-1. On the other hand, COX-2 is usually undetectable in healthy tissue but is triggered by lipopolysaccharides or cytokines in inflammatory situations. While many of the negative effects of NSAIDs are mostly caused by the suppression of COX-1, they also have an anti-inflammatory effect by inhibiting COX-2.

Prostaglandin Eicosanoid-2(PGE2) and Its Contribution to Mucosal Defence

Arachidonic acid is a fatty acid that is used to make prostaglandins, which resemble hormones. Prostaglandin E2, Prostacyclin (PGI2), Prostaglandin D2 (PGD2), and Prostaglandin F2a (PGF2a) are the four main forms. According to Ricciiotti Fitze-Gerald et al. [49], prostaglandin E2 is the primary eicosanoid and serves a number of purposes, including protecting the stomach, regulating inflammation, promoting conception (by inducing uterine contractions through dinoprostone), lowering blood pressure, and participating in immune cell communication and overall immunity. The stomach mucosa of humans and rodents mostly produces PGE2 and PGI2, with smaller levels of PGF2a and PGD2 [50]. The gut has high amounts of PGE2 and PGI2, which shield the small intestine and stomach from harm [51]. PGE2 levels are decreased in ulcer patients in their abdomens, compared to people in good health. Aspirin and other NSAIDs lower prostaglandin synthesis, which damages the stomach and increases the risk of ulcers [52].

According to Takezono et al. [53], prostaglandins cause epithelial cells to secrete more mucus and bicarbonate, which decreases the epithelium's permeability and, consequently, acid back-diffusion. Gastric acid secretion can be inhibited by prostaglandins [50]. Because prostaglandins are strong vasoconstrictors, they can increase mucosal blood flow, which makes the stomach mucosa more resilient to damage. According to Wallace et al. [50], prostaglandins produced from COX-1 are primarily responsible for baseline mucosal blood flow, but prostaglandins derived from COX-2 are more crucial in situations where mucosal integrity is compromised, such as during ischemia-reperfusion injury. Because prostaglandins can reduce inflammatory reactions, they can make the stomach mucosa more resilient to damage. For instance, PGE2 prevents mast cells from releasing histamine, tumour necrosis factor-α, interleukin 8, leukotriene B4, and platelet-activating factor. Several of these inflammatory mediators have been found to increase the vulnerability of the stomach to injury, produced by NSAIDs [50]. PGE2 has been shown to inhibit the production of H+ ions and pepsinogen in the stomach, which lowers the amount of gastric secretion and its acid and peptic activity. However, the primary effect is an increase in mucus and bicarbonate production, stimulation of cell proliferation processes, and physiological regeneration of the gastric mucosa's epitheliocytes. Accordingly, a reduction in PG production is linked to a reduction in the stomach mucosa's resistance [54].

Additionally, leukocyte adhesion to the vascular endothelium is strongly inhibited by prostaglandins [55]. In fact, prostaglandin treatment can stop the leukocyte adherence that takes place in the gastrointestinal microcirculation after NSAID administration [56]. And this probably plays a part in prostaglandins' ability to shield the stomach mucosa [57].

According to the aforementioned research, prostaglandins play a significant role in mucosal defense; consequently, NSAID-induced prostaglandin suppression may result in gastrointestinal injury, as will be covered below.

NSAID-Induced Prostaglandin Eicosanoid-2 (PGE2) Inhibition and Its Effect on Gastric Mucosa

NSAIDs prevent prostaglandin synthesis by blocking COX. While COX 2 produces prostaglandins that mediate inflammation and discomfort in various parts of the body, COX 1 produces prostaglandins that are involved in the protection of gastrointestinal mucosa [59]. NSAIDs primarily work by inhibiting prostaglandin. This is because prostaglandins mediate pain and inflammation; therefore, inhibiting them will lessen their symptoms. 1-4% of individuals who take NSAIDs on a long-term basis experience clinically severe ulceration, bleeding, and/or blockage [59]. There are two types of mechanisms by which NSAIDs cause stomach damage: systemic effects and local (topical) actions.

SYSTEMIC ACTION: NSAIDs' capacity to inhibit prostaglandin synthesis is the most significant of their systemic actions when it comes to causing stomach ulcers. The mucosa is more vulnerable to the harmful effects of luminal substances (acid, pepsin, ethanol, etc.) and, in certain situations, the NSAID itself when gastric prostaglandin synthesis is suppressed. When an NSAID is administered, or even if mucosal blood flow is briefly interrupted, the surface injury quickly turns into hemorrhagic, erosive damage that penetrates the entire thickness of the mucosa. By administering a prostaglandin, this NSAID effect can be avoided [57]. Reducing mucosal blood flow was one of the first known effects of NSAIDs on the stomach mucosa [60]. This impact is now understood to be dependent on the amount of acid in the lumen [61] and to be mainly caused by the inhibition of COX-1 activity stated [57]. Usually, the amount of stomach blood flow reduction is insufficient on its own to cause serious mucosal damage. As previously mentioned, decreased mucosal blood flow will hinder the process of epithelial restoration and make the mucosa more vulnerable to damage caused by luminal irritants [50]. A significant observation was made by Kitahora et al. [62]. Shortly after the stomach was exposed to aspirin, they observed "white thrombi" along the vessel walls in the gastric microcirculation. In the places where the thrombi were seen, mucosal blood flow subsequently dropped, and eventually the same areas developed hemorrhagic symptoms. Assuming that Kitahora and Guth's white thrombi were neutrophils, it is possible that neutrophils played a significant role in the pathophysiology of NSAID-induced stomach damage. The endothelium damage that happens shortly after NSAID administration may be caused by neutrophils [50]. It has been discovered that the administration of NSAIDs causes leukocytes, mainly neutrophils, to attach to the vascular endothelium. The time course of leukocyte adherence after NSAID treatment matched the time course of prostaglandin production inhibition, and prostaglandin injection could stop the NSAID-induced leukocyte adherence [56]. NSAIDs' actions on platelets contribute to their impairment of ulcer healing. The healing of ulcers is significantly aided by platelets. The production of VEGF, a powerful stimulant of new blood vessel growth (angiogenesis), a crucial component in the ulcer healing process, is probably linked to the positive effects of platelets on ulcer healing. Rats' ulcers can heal more quickly when a platelet suspension is given orally; this effect can be counteracted by preincubating the platelet suspension with an antibody that targets VEGF [57].

TOPICAL ACTION: NSAIDs may act topically on the stomach epithelium through a variety of methods. Certain NSAIDs can directly destroy epithelial cells, especially those that are acidic. Additionally, NSAIDs can lower mucus and bicarbonate secretion, which lessens the juxta-mucosal pH gradient's ability to shield the epithelium [63]. Regardless of how they affect prostaglandin formation, NSAIDs can potentially damage the layer of surface-active phospholipids on the mucosal surface. This would make the mucosa less resilient to luminal acid-induced injury [64]. Additionally, NSAIDs may reduce EGF's capacity to support epithelial healing. Therefore, NSAID exposure has been shown to reduce epithelial proliferation, which seems to include a decrease in EGF binding to its receptor [65]. Although the aforementioned processes probably play a role in NSAID toxicity in the stomach, they are not likely to be the only cause of ulcer development. For instance, parenteral administration of NSAIDs can result in gastric ulcers [66]. If an NSAID is excreted in bile, it may reflux into the stomach and harm the epithelium. However, it has been shown that intravenous administration of aspirin, which is not eliminated in bile ([67], can cause stomach ulcers in cats [68]. The finding that the incidence of severe gastric ulceration and bleeding is not significantly decreased when the NSAIDs are enteric-coated to prevent direct contact of the NSAID molecule with the gastric mucosa or when the NSAIDs are formulated as a prodrug that is inactive until metabolized in the liver further supports an important contribution of non-topical actions of NSAIDs to ulcer formation [34].

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