Peptic Ulcers

Peptic Ulcers

1 Overview

Summary and Quick Facts

  • Peptic ulcers are sores in the lining of the stomach, or first part of the small intestine. They can cause burning pain in the upper abdomen, vomiting or heart burn. Sometimes, ulcers do not cause any symptoms.
  • This protocol describes the causes of ulcers, such as too many anti-inflammatory drugs (NSAIDs) like ibuprofen or infection with H. pylori bacteria. Learn about treatment options for ulcers, which depend on cause, and dietary and lifestyle changes that can reduce ulcer risk, such as reducing alcohol consumption.
  • A particular kind of licorice extract called DGL has been shown in help eradicate H. pylori infections and reduce gastrointestinal bleeding caused by aspirin.

A peptic ulcer is a sore in the lining of the stomach, where it is called a gastric ulcer, or the first part of the small intestine, called a duodenal ulcer. In the United States, roughly 4.5 million people suffer from peptic ulcer disease.

Fortunately, integrative interventions including deglycyrrhizinated licorice (DGL), zinc-carnosine, and Lactobacillus reuteri have powerful ulcer-healing effects.

Causes and Risk Factors

  • H. pylori infection, the primary cause
  • Non-steroidal anti-inflammatory drugs (NSAIDs), the second-leading cause
  • Stomach acid
  • Alcohol
  • Cigarette smoking

Symptoms

  • Up to 40% of those with ulcers have no symptoms
  • A gnawing or burning pain , nausea, vomiting, or heartburn

Complications

  • Bleeding internally, which is the most common complication.
  • Perforation, in which ulcers break through the wall of the duodenum or stomach.
    • Note: This is a medical emergency requiring surgical intervention.

Diagnosis

  • Upper gastrointestinal endoscopy, a camera inserted on a long tube down to the stomach, is necessary for a conclusive diagnosis of peptic ulcer. Endoscopy allows inspection and biopsy of the stomach and duodenum and detection of H. pylori.
  • A CBC and stool occult blood tests are recommended for patients suspected of having a bleeding ulcer.

Conventional Treatment

  • H. pylori-positive ulcers
    • Antibiotics result in a 70‒90% cure rate.
      • Note: Antibiotic resistance is a growing problem in Canada and the United States.
    • Proton-pump inhibitors (PPIs) block the secretion of stomach acid, allowing ulcers to heal and often relieving pain.
      • Note: When used long-term, PPIs are associated with a wide range of serious side effects including kidney and cardiovascular disease.
    • Triple-therapy is a standard treatment that combines two antibiotics and a PPI. Bismuth may also be included for “quadruple therapy.”
  • H. pylori-negative ulcers
    • NSAID use should be discontinued. Antacids and medications that reduce acid secretion are used in these situations.
    • Misoprostol (Cytotec) and sucralfate (Carafate) are used to help protect the stomach lining against the damaging effects of NSAIDs in patients who must continue to take them.

Novel and Emerging Strategies

  • Silver nanoparticles. Laboratory and animal studies indicate silver nanoparticles have anti-H. pylori activity.
    • Note: Silver nanoparticles should not be confused with over-the-counter colloidal silver preparations. Colloidal silver has not been proven effective for treating any condition, and may have several side effects, including argyria—a disorder in which the skin takes on a permanent bluish-gray discoloration.
  • Liposomal linolenic acid. Liposomal linolenic acid has been shown to kill H. pylori and markedly reduce its population in the stomach of mice. In addition, liposomal linolenic acid was shown to decrease levels of pro-inflammatory cytokines triggered by H. pylori.

Dietary and Lifestyle Considerations

  • A diet rich in fruits, vegetables, and fiber may reduce the risk of ulcers by 50%, and also help heal existing ulcers.
  • Fermented dairy products such as yogurt and kefir appear to promote H. pylori eradication.
  • Stress management is important as stress and tension is correlated with gastric and duodenal ulcers.

Integrative Interventions

  • Deglycyrrhizinated licorice (DGL). In a trial, 100 patients who tested positive for H. pylori were treated with DGL or placebo for 30 days. At the end of the treatment period, 56% of the DGL group and 4% of the placebo group tested negative for H. pylori.
  • Zinc-carnosine. In a randomized clinical trial, 86% of subjects treated with triple therapy alone achieved eradication while 100% treated with triple therapy plus zinc-carnosine (150 mg twice daily) were H. pylori-negative four weeks after treatment.
  • Lactobacillus reuteri. L. reuteri DSM17648 supplements have been shown to decrease the H. pylori load in healthy H. pylori-positive individuals, and may thus prevent future H. pylori-associated problems, including the need for antibiotic treatment.
  • Lactoferrin. A meta-analysis examined five randomized controlled trials that evaluated whether lactoferrin treatment was effective for H. pylori eradication. Those who received lactoferrin had more than 2.2-fold higher odds of eradication compared with controls.
  • Flavonoids/polyphenols. Evidence from numerous studies indicate polyphenols, including flavonoids, hold promise in the prevention and treatment of peptic ulcers. Extracts from tea, apples, pomegranate, and grape seed are especially good sources of polyphenols with possible anti-ulcer and anti-H. pylori activity.

2 Introduction

A peptic ulcer is a sore in the lining of the stomach or the first part of the small intestine. Ulcers in the stomach are called gastric ulcers, and those in the upper small intestine are called duodenal ulcers. Symptoms include pain, nausea, vomiting, and heartburn; in serious cases, ulcers may cause bleeding into the stomach or perforation of the gastrointestinal wall (Ferri 2016; DiMarino 2016a; Kuipers 2012).

In the United States, roughly 4.5 million people suffer from peptic ulcer disease, and about 500,000 new cases are reported each year (Ferri 2016; Anand 2017).

The most common causes of peptic ulcers are infection with the bacterium Helicobacter pylori and use of nonsteroidal anti-inflammatory drugs (NSAIDs) (Kuipers 2015).

Uncomplicated ulcers associated with H. pylori infection are usually treated with antibiotics plus a proton-pump inhibitor (PPI), which reduces gastric acid secretion and allows the ulcer to heal. Treatment of bleeding ulcers may require endoscopic surgery (Kuipers 2015; Lee 2013).

Increasing use of antibiotics in children over the past several decades has led to a decline in the prevalence of H. pylori infection among younger generations, and combination therapy with antibiotics and PPIs is very effective in treating peptic ulcers (Malfertheiner 2009; Kuipers 2012). However, antibiotic resistance now represents a critical factor in the failure of ulcer treatment (Homan 2015; Yaxley 2014). Thus, new methods for eradicating H. pylori and treating ulcers are needed.

The good news is that new scientific discoveries may improve the efficacy of ulcer treatment. For instance, integrative interventions including deglycyrrhizinated licorice (DGL), zinc-carnosine, and vitamin C have powerful anti-H. pylori and ulcer-healing effects (Puram 2013; Watari 2013; Pal 2011). Probiotics, particularly a strain called Lactobacillus reuteri DSM17648, appear to help control H. pylori and reduce the inflammatory response to infection with this organism. Treatment with probiotics can also enhance the ability of antibiotics to eliminate H. pylori infection, while reducing drug side effects (Boltin 2016; Homan 2015; Holz 2015).

In addition, lifestyle and dietary changes can have a profound impact on ulcer risk and promote ulcer healing. Smoking cessation, stress reduction, and avoidance of NSAIDs and excess alcohol all help promote ulcer healing and prevent recurrence (Lee 2013; Han 2002; Ferri 2016). A diet rich in fiber and plant phytonutrients called polyphenols can protect against development of peptic ulcers as well (Farzaei 2015; Ryan-Harshman 2004).

In this protocol, you will learn about the causes of peptic ulcers and how they are typically treated. Several emerging treatment techniques will be reviewed, and a number of dietary and lifestyle changes that may reduce ulcer risk will be discussed. In addition, many natural integrative interventions that may help keep the gastric and intestinal mucosa healthy will also be reviewed.

3 Causes And Risk Factors

The lining of the stomach and intestine is covered by a thick mucus layer that functions as a physical barrier between the outside environment and the body (Chai 2011). The formation of peptic ulcers results from disruption of the mucosal barrier by factors such as stomach acid, pepsin, H. pylori infection, non-steroidal anti-inflammatory drugs (NSAIDs), alcohol, and cigarette smoking (Ferri 2016).

Gastric ulcers develop in the lining of the stomach. Pain from a gastric ulcer may be aggravated or alleviated by eating. Duodenal ulcers form in the first few centimeters of the lining of the duodenum (the upper part of the small intestine). Pain associated with duodenal ulcers is typically relieved by eating but often returns two to three hours later, and frequently awakens patients at night (DiMarino 2016a).

Helicobacter pylori infection. H. pylori infection is the primary cause of peptic ulcer disease; it is present in 30% to 50% of patients with gastric ulcers and 50% to 70% of those with duodenal ulcers (Kuipers 2015; DiMarino 2016a).

H. pylori bacteria bore into the protective mucus layer of the stomach or small intestine (duodenum) and cause an inflammatory response. Chronic inflammation induced by H. pylori damages the mucosa and disrupts pH regulation. These effects can lead to ulcer formation (UMMC 2015; Chai 2011). H. pylori infection can also increase the risk of gastric cancer (Waldum 2014).

Nonsteroidal anti-inflammatory drugs (NSAIDs). Chronic use of NSAIDs such as ibuprofen, naproxen, and aspirin is the second-leading cause of peptic ulcer disease, and the occurrence of NSAID-related ulcers is increasing, particularly in older individuals (UMMC 2015; Kuipers 2012).

By inhibiting cyclooxygenase (COX) enzymes, NSAIDs cause a decrease in the synthesis of prostaglandins that stimulate production of protective mucus and acid-buffering bicarbonate in the digestive tract. This increases vulnerability to ulcer formation. NSAIDs also increase risk of gastrointestinal bleeding (Chai 2011; UMMC 2015).

Our Complex Relationship with Helicobacter pylori

The association of H. pylori with peptic ulcer disease was discovered in 1984, and this discovery has fundamentally altered the treatment, as well as the prevalence, of peptic ulcers (Owyang 2011; Malfertheiner 2009; Kuipers 2012). However, only 10‒15% of adults infected with H. pylori ever develop peptic ulcers—additional factors are necessary to trigger disease (UMMC 2012; Malfertheiner 2009; Owyang 2011). In addition, more recent discoveries have found that H. pylori may be protective against asthma and allergy, inflammatory bowel disease, gastroesophageal reflux disease (GERD), esophageal cancer, and obesity, which suggests that, at least for some, there may be a benefit to colonization with this microbe (Owyang 2011; Chen 2007; McNeil 2008; Malfertheiner 2010).

While H. pylori has inhabited the human digestive tract for well over 50 000 years (Owyang 2011), peptic ulcer disease is believed to be a relatively recent phenomenon of the past two centuries, associated with changes in diet and lifestyle (Graham 2014). In recent decades, the prevalence of H. pylori colonization has been on the decline in Western societies, possibly resulting from rising standards of living, improved hygienic conditions, and broader use of antibiotics (Kuipers 2012; den Hoed 2011).

Some researchers believe these dualistic properties of H pylori—to both cause peptic ulcer disease and gastric cancer under some conditions while possibly protecting against other diseases—deserve serious scientific attention. Specifically, scientists speculate that the host-microbe interaction is of critical importance, and a new concept should replace the idea that H. pylori is always harmful and should be eradicated even in asymptomatic individuals. It has even been proposed that inoculation with H. pylori might be beneficial in certain individuals (Blaser 1998; Blaser 2008). Continuing research in this field promises to increase our understanding of the role of H. pylori in health and disease, as well as of the importance of each individual’s host-microbe relationship.

Additional Risk Factors

  • Age and gender. Ulcers can develop at any age, but are most common in middle-aged adults. Men are twice as likely as women to develop ulcers (UMMC 2015).
  • Smoking. Cigarette smoking increases the risk of ulcers, increases the rate of recurrence, and delays ulcer healing (DiMarino 2016a).
  • Alcohol abuse. Alcohol use promotes secretion of stomach acid and damages the gastric mucosa; heavy drinkers are at increased ulcer risk. Light-to-moderate drinking has not been definitively linked to ulcers (Lee 2013; DiMarino 2016a).
  • Family history. Risk of ulcers is higher in those with a relative who has a history of peptic ulcers (Lee 2013).
  • Previous history of ulcers. About 80% of individuals with bleeding ulcers have had symptomatic ulcers in the past (Kuipers 2012).
  • Stress. Stress is correlated with peptic ulcer disease and may compound the effects of H. pylori infection (Overmier 2013; Herszenyi 2015).
  • Medication combinations. The combination of NSAIDs with corticosteroids, bisphosphonates, and certain other medications is associated with an increased risk of peptic ulcers (Lee 2013).

4 Symptoms And Complications

Common Symptoms

Up to 40% of all patients with uncomplicated peptic ulcer disease do not have symptoms. Older people in particular are likely to be symptom free (DiMarino 2016a; Kuipers 2012).

Pain is the most common symptom of peptic ulcer disease, and is often felt in the upper abdomen. It is often described as gnawing, burning, or tenderness that may be relieved by food or antacids (Lee 2013; DiMarino 2016a). Because ulcer pain may radiate to the back, chest, and other parts of abdomen, it is sometimes mistaken for other problems, including a heart attack (Ferri 2016; UMMC 2012). Pain that disrupts nighttime sleep often indicates a duodenal ulcer (DiMarino 2016a).

Other possible symptoms include nausea, vomiting, and heartburn. Severe abdominal pain, loss of appetite, weight loss, black or bloody stools, and vomiting that may include blood could indicate an ulcer complicated by bleeding or perforation; anyone experiencing these symptoms should seek medical care immediately (Kuipers 2012).

Complications

Bleeding internally is the most common complication, occurring in up to 15% of patients with peptic ulcer disease. Ulcers caused by NSAIDs are more likely to bleed than those caused by H. pylori (UMMC 2012; Milosavljevic 2011).

Perforation, in which ulcers breach the wall of the duodenum or stomach, causing damage to nearby tissues and organs, occurs more commonly in older patients and is a medical emergency requiring surgical intervention. Perforation occurs in 2% to 10% of peptic ulcers. When perforation directly affects an organ it is called penetration (Ramakrishnan 2007; Meyer 2015).

Obstruction that blocks stomach emptying can result from inflammation, spasm, or scarring from recurrent ulcers. Symptoms of obstruction include repeated vomiting as well as sustained fullness and bloating after eating (Ramakrishnan 2007; Meyer 2015).

H. pylori-associated peptic ulcer disease increases by three- to six-fold the risk of developing stomach cancer later in life (DiMarino 2016a).

5 Diagnosis

The diagnosis of peptic ulcer disease begins with a physical examination and a thorough medical and family history. The exam and history help rule out disorders that may cause similar symptoms, including gastroesophageal reflux disease (GERD), heart attack, gallstones, irritable bowel syndrome, and cancer (Ferri 2016; Lee 2013).

Upper gastrointestinal endoscopy is necessary for a conclusive diagnosis of peptic ulcer. Endoscopy allows inspection of and biopsy of the stomach and duodenal lining as well as direct culture for H. pylori. Biopsy is necessary to distinguish peptic ulcer from ulcerative malignancy. Immediate endoscopy is recommended for patients with signs of gastrointestinal bleeding, and for urgent symptoms including excessive vomiting, difficulty swallowing, and excessive weight loss (Ramakrishnan 2007; Anand 2017; DiMarino 2016a; Kuipers 2012). A complete blood count (CBC) and stool occult blood tests are recommended for patients suspected of having a bleeding ulcer (Lee 2013).

All patients with suspected peptic ulcer disease should be tested for H. pylori. Techniques that can detect H. pylori infection include blood tests to measure H. pylori antibodies, a urea breath test, and a stool antigen test (Ferri 2016; Lee 2013). Additionally, follow-up testing one to two weeks after completion of treatment should be used to confirm that H. pylori has been successfully eradicated (Chey 2017).

6 Conventional Treatment

The presence or absence of H. pylori infection is the critical determinant of ulcer treatment. Beyond eradication of H. pylori, symptom relief and promotion of ulcer healing are the main treatment objectives for uncomplicated peptic ulcers. Complications such as uncontrolled or recurrent bleeding, perforation, and obstruction may require surgery (Lee 2013; Ramakrishnan 2007; DiMarino 2016a).

H. pylori-Positive

The 2017 clinical guideline from the American College of Gastroenterology for the treatment of H. pylori recommends as first-line treatment either a combination of three antibiotics and a proton pump inhibitor (PPI) medication or “bismuth quadruple therapy” which uses a bismuth preparation, two antibiotics, and a PPI. Multiple variations of treatment based on these or similar combinations of drugs may also be considered. All recommended treatments are of 10‒14 days duration (Chey 2017).

  • Antibiotics. Eradication of H. pylori by antibiotics is the mainstay of treatment for peptic ulcers associated with H. pylori, and results in a 70‒90% cure rate (UMMC 2012; Lee 2013). Recommended first-line treatment combinations include clarithromycin (Biaxin), a nitroimidazole such as metronidazole (Flagyl), and amoxicillin; or tetracycline and a nitroimidazole (Chey 2017).

    Clarithromycin resistance plays an important role in the variable estimates of cure rates for H. pylori and peptic ulcer. This is a growing problem in the United States and Canada. Resistance to metronidazole and levofloxacin (Levaquin) has also been documented (Chey 2017).

  • Proton pump inhibitors (PPIs). PPIs are drugs that block the secretion of stomach acid, allowing ulcers to heal and often relieving pain (DiMarino 2016b). PPIs also enhance the efficacy of antibiotics in H. pylori eradication (Lee 2013). PPIs used for this purpose include omeprazole (Prilosec), lansoprazole (Prevacid), esomeprazole (Nexium), and rabeprazole (AcipHex) (UMMC 2012).

    H. pylori eradication regimens are generally brief, lasting 10‒14 days. However, when used long-term, PPIs are associated with a wide range of serious side effects including kidney and cardiovascular disease (see “Potential Risks of Long-term Proton Pump Inhibitor (PPI) Use”).

  • Bismuth. Bismuth-containing medications (eg, Pepto-Bismol, Kaopectate) reduce gastrointestinal acidity and improve the efficacy of standard antimicrobial therapy against H. pylori. Bismuth rarely causes systemic side effects, but can result in black and tarry stools (UMMC 2012; Lee 2013).

Salvage therapy is sometimes used when initial therapy fails; this strategy uses different antibiotics than those that previously failed. Bismuth quadruple therapy or regimens containing levofloxacin are preferred salvage regimens (Chey 2017).

In addition to antibiotic resistance, poor compliance is an obstacle to effective treatment. Triple and quadruple therapies are complicated, expensive, and cause side effects (mostly digestive) in about 30% of patients (UMMC 2015; Safavi 2016).

In most patients, drug therapy relieves ulcer symptoms, but in some cases, symptoms persist despite effective clearing of H. pylori. Long-term management of dyspepsia with acid-suppression or other treatments may be helpful in these cases (Lee 2013).

H. pylori- Negative

For patients with peptic ulcers who test negative for H. pylori, NSAID use should be discontinued if possible. Antacids and medications that reduce acid secretion including PPIs are used in these situations (Lee 2013; Ferri 2016):

Antacids. Antacids neutralize stomach acid. Antacids containing bismuth subsalicylate (eg, Pepto-Bismol, Kaopectate), calcium carbonate (eg, Tums), and a combination of aluminum hydroxide and magnesium hydroxide (Maalox, Mylanta) are available over the counter. These drugs usually cause only mild side effects, including diarrhea or constipation (IFFGD 2015; NCBI 2007).

H2 receptor antagonists. H2 receptor antagonists block the acid-stimulating action of histamine in the stomach. Examples include cimetidine (Tagamet), famotidine (Pepcid AC), and ranitidine (Zantac). They are available over the counter, but a prescription is required for higher doses. Serious side effects caused by H2 receptor antagonists are rare but more common in older patients (DiMarino 2016b; UMMC 2012; NLM 2017b). H2 receptor antagonists can reduce vitamin B12 absorption, so B12 status should be monitored in long-term users, and B12 supplementation should be initiated if a B12 deficiency is detected (Force 1992).

Mucosal protective agents. Misoprostol (Cytotec) and sucralfate (Carafate) are used to help protect the stomach lining against the damaging effects of NSAIDs in patients who must continue to take them. Misoprostol stimulates prostaglandin production, and can prevent NSAID-related ulcer, but does not heal existing ulcers. Misoprostol also inhibits stomach acid and pepsin production (CIHR 2017). Misoprostol causes diarrhea and other gastrointestinal side effects relatively frequently, and is contraindicated in pregnant women because it can cause miscarriages and birth defects (Lee 2013; Ferri 2016; UMMC 2012). Sucralfate forms a chemical barrier at ulcerated sites to protect against further damage. Sucralfate occasionally causes constipation but has few side effects, though it does interfere with a number of different medications (Gold Standard 2013; UMMC 2012).

Maintenance Therapy

Maintenance therapy is recommended for patients who experience recurrent ulcers. Maintenance therapy generally involves long-term use of antacids, H2 receptor antagonists, mucosal protectants, or PPIs. Although PPIs are usually considered the most effective maintenance treatment (Ferri 2016), long-term PPI use is associated with an array of grave health consequences and an increased risk of death (Maggio, Corsonello 2013; Shih 2014; Klepser 2013).

Potential Risks of Long-term Proton Pump Inhibitor (PPI) Use

Although proton-pump inhibitor (PPI) drugs are widely used, they are associated with a number of potentially serious outcomes. Moreover, many people may use PPIs for longer than the directed usage, which may exacerbate side-effect risk. Over-the-counter PPIs should not be used for more than three 14-day treatment periods each year (FDA 2016b), and prescription PPIs should be used as directed, usually no more than eight weeks (JAGS 2015).

Long-term use of PPIs—more than four to eight weeks—may lead to physiological deficiencies of important micronutrients such as calcium, magnesium, and vitamin B12. These deficiencies increase the risk of a host of conditions such as musculoskeletal and neurological abnormalities, heart rhythm irregularities, and increased risk of cardiovascular disease and diabetes (Atkinson 2015; Yang 2012; Linder 2016).

Other observational associations with PPI use include:

Risk of death. Several studies have found that PPI use is associated with increased risk of death from any cause (Maggio, Corsonello, Ceda 2013; Teramura-Gronblad 2012). In one study that enrolled 491 patients with an average age of 80 years, PPI use was independently associated with a 51% increased risk of dying during a one-year period; those on high-dose PPI therapy (20‒40 mg daily) had an almost 2.6-fold increased risk of dying within one year (Maggio, Corsonello, Ceda 2013).

Heart attack. PPI use has been associated with heart attacks in several studies, though a causal relationship between PPI use and heart attack has not been established (Fusaro 2013; Shah 2015). One study of over 126,000 PPI users and an equal number of nonusers found PPI use was linked to a 58% increased risk of heart attack over a 4-month period (Shih 2014; Fusaro 2013; Shah 2015).

Kidney disease. PPI use has been associated with kidney damage and chronic kidney disease (Antoniou 2015; Lazarus 2016). One study in over 184,000 individuals found that those with kidney disease were twice as likely to have used a PPI (Klepser 2013).

Pneumonia. PPI use appears to increase the risk of community-acquired pneumonia (Giuliano 2012). PPIs may increase pneumonia risk by several mechanisms: 1) inhalation of pathogens from the digestive tract that would normally be killed in more acidic conditions; 2) changes in the normal bacterial population of the airways due to acid reduction in the respiratory tract; and 3) PPIs directly impair immune cell function (Ho 2015; Lambert 2015).

Clostridium difficile infection. Clostridium difficile is a bacterium that can cause potentially severe intestinal infections (NLM 2017a). PPI users who also take antibiotics have a particularly pronounced risk of C. difficile infection (Kwok 2012; Janarthanan 2012). The Food and Drug Administration (FDA) has issued a warning to patients taking PPIs that they should contact their healthcare provider immediately if they develop diarrhea that does not improve (FDA 2016a).

Fractures and osteoporosis. Several studies have correlated long-term use of PPIs with increased risk of fractures, including fractures of the hip, spine, and wrist (Gray 2010; Lau 2012). Impairment of calcium absorption is one factor that may contribute to the increased fracture risk observed with prolonged PPI use (Fournier 2009).

Disturbance of gastrointestinal flora. PPIs alter the populations of microorganisms that inhabit the gastrointestinal tract. This can lead to small intestinal bacterial overgrowth, which may increase susceptibility to NSAID-induced injury to the small intestinal mucosa (Fujimori 2015; Lombardo 2010). Alterations in gut microbial composition are also implicated in an observed link between PPI use and celiac disease, though more research is needed to firmly establish the influence of PPI use on celiac risk (Freedberg 2014).

Development of hypersensitivities. Gastric acid normally breaks down potentially immunogenic proteins in food, but acid suppressive therapy may hinder this process, causing reactive particles to pass into the intestine and trigger an immune response (Trikha 2013). Studies have demonstrated an increased incidence of hypersensitivity reactions to both foods and drugs in PPI users. In hospitalized patients, those taking PPIs were nearly 4 times as likely to develop drug hypersensitivity reactions (Trikha 2013; Ramirez 2013). More rigorous prospective research is needed to establish the degree of causality in this relationship.

People who use PPIs for more than eight weeks should consult with a qualified healthcare provider to discuss risks and benefits. In some cases, long-term risks may outweigh potential benefits and therapy should be discontinued or adjusted—each case is unique and healthcare providers should take the patient’s complete health history into consideration.

7 Novel And Emerging Strategies

Silver Nanoparticles

Silver compounds have antibacterial activity through multiple mechanisms, which lowers the likelihood of microbial resistance. Silver nanoparticles gained attention in recent years as a potential tool in the battle against antibiotic-resistant organisms (Dakal 2016). Utilizing silver compounds to target H. pylori represents one such opportunity.

Laboratory and animal studies indicate silver nanoparticles have anti-H. pylori activity (Amin 2012; Kuo 2014). In one animal model, silver nanoparticles were shown to safely decrease H. pylori densities, with higher silver concentrations having stronger inhibitory effects (Kuo 2014).

Silver nanoparticles could potentially be used to lower H. pylori load, increasing the success of anti-H. pylori therapies. Human studies with longer observation periods are needed before clinical use becomes practical (Kuo 2014).

Note: silver nanoparticles should not be confused with over-the-counter colloidal silver preparations. Silver nanoparticle preparations are used in experimental settings under controlled conditions and have different physicochemical properties than readily available colloidal silver preparations. Colloidal silver preparations have not been demonstrated in published, peer-reviewed studies to have anti-H. pylori activity. In addition, colloidal silver has not been proven effective for treating any condition, and may have several side effects, including argyria—a disorder in which the skin takes on a permanent bluish-gray discoloration (Griffith 2015; NIH 2017).

Liposomal Linolenic Acid

Linolenic acid is a naturally occurring fatty acid found in vegetable oils that has antimicrobial properties. However, under normal conditions in the body, linolenic acid is not soluble and has little antibacterial activity. Liposomal technology overcomes this barrier by incorporating linolenic acid into a complex of cholesterol and phospholipids. This creates microscopic particles called liposomes that fuse with H. pylori cell membranes and efficiently deliver linolenic acid (Thamphiwatana 2014; Jung 2015).

Liposomal linolenic acid has been shown to kill H. pylori and markedly reduce its population in the stomach of mice. In addition, liposomal linolenic acid was shown to decrease levels of pro-inflammatory cytokines triggered by H. pylori (Thamphiwatana 2014).

In mice, liposomal linolenic acid was found to penetrate the gastric mucus layer where H. pylori resides (Allen 1997). A considerable amount of liposomal linolenic acid remained in the stomach lining up to 24 hours later, and no toxic effects of this treatment were observed (Thamphiwatana 2014).

Intermittent Oral Proton-Pump Inhibitor Therapy for Bleeding Ulcers

Acid suppression with PPIs reduces bleeding, although the exact mechanism behind this effect is not well understood. For patients with high-risk bleeding ulcers, current guidelines recommend a single intravenous dose of a PPI followed by continuous PPI infusion for 72 hours after endoscopic treatment. However, according to a review of studies, intermittent treatment with both oral and intravenous PPIs are as effective as continuous infusion of PPIs in patients with high-risk bleeding ulcers. Intermittent PPI therapy (oral or intravenous) has the advantages of easy administration, lower cost, and lower PPI dose than continuous infusion PPI therapy (Sachar 2014). Also, intermittent PPI therapy has been shown to reduce the total amount of PPI used, which may reduce long-term side effects, although this has not been firmly established (Laine 2016).

8 Dietary And Lifestyle Considerations

Diet

A diet rich in fruits and vegetables and fiber may reduce the risk of ulcers by 50%, and also help heal existing ulcers (Ryan-Harshman 2004; UMMC 2012).

Polyphenols, naturally occurring compounds present throughout the plant kingdom, are obtained from the diet, mostly from fruits, vegetables, spices, grains, coffee, tea, and wine (Cardona 2013). Polyphenols have considerable anti-ulcer potential. Preclinical, animal, and clinical studies have shown that polyphenols may influence ulcer formation and healing through modulation of inflammation, ulcer-healing qualities, and anti-H. pylori activity (Farzaei 2015).

Among the polyphenols that have demonstrated gastro-protective activity in preclinical studies are quercetin (found in onions, apples, and many other plant foods); curcumin (found in turmeric); epigallocatechin gallate (EGCG) and catechins (found especially in green and black tea); and anthocyanins (found especially in red grapes, grape juice, red wine, cranberries, and other red and purple produce) (Farzaei 2015; Mota 2009).

Polyphenols protect against ulcers by mechanisms including protection against free radical damage; fortifying mucosal defense by stimulating production of mucus, growth factors, and prostaglandins; diminishing stomach acid secretion; increasing mucosal blood flow; and exerting antibacterial activity against H. pylori (Farzaei 2015; Mota 2009).

Two clinical trials have found an anti-H. pylori effect of virgin olive oil (Castro 2012). In a preclinical study, polyphenols from virgin olive oil showed antibacterial activity against eight different strains of H. pylori (Romero 2007).

Extracts of the spices garlic, ginger, and turmeric have exhibited anti-ulcer activity in animal models of peptic ulcer, an effect that may result from protection of the mucosa against oxidative injury and inflammation (Choi 2014; Zaghlool 2015; Liju 2015). Ginger extract and curcumin have demonstrated anti-H. pylori activity in preclinical studies (Mahady 2003; Mahady 2002).

Dairy and Peptic Ulcers

Long before the advent of modern ulcer treatment with acid-suppressing agents and antibiotics, drinking milk was commonly recommended for ulcers (UMMC 2015). In fact, in the early 20th century, a new treatment for ulcers was introduced which consisted of hourly consumption of milk and cream along with a mixture of sodium bicarbonate (baking soda) plus a calcium-magnesium or bismuth compound. The goal of this treatment was to neutralize stomach acid in order to allow the ulcer to heal (Patel 2013; Sippy 1915). Within a couple of decades, it was discovered that this treatment led to excessive blood calcium and metabolic alkalinity, and kidney injury. This came to be called milk alkali syndrome (Medarov 2009; Cope 1936).

Interestingly, preclinical, animal, and clinical studies have shown that some milk components such as milk protein and fat have gastroprotective properties. One randomized controlled trial found that milk fermented with Bifidobacterium bifidum was superior to placebo for symptom relief (Miki 2007; Ushida 2007; Dial 1995; Dial 1987). Fermented dairy products such as yogurt and kefir appear to promote H. pylori eradication (Sachdeva 2014). However, milk has also been shown to delay the healing rate of duodenal ulcers, and is no longer recommended for ulcer patients as it likely stimulates increased stomach acid production (CCF 2017; Kumar 1986).

Smoking Cessation

Smokers are at twice the risk of ulcers as non-smokers. Cigarette smoking increases the chances of developing H. pylori infection, delays healing of ulcers, and makes ulcer recurrence more likely (NIH 2013; Lee 2013). Smoking cessation provides immediate benefit for ulcer healing (Parasher 2000; Eastwood 1988).

Alcohol Reduction

Alcohol can cause direct physical injury to the stomach lining and increase gastric acid secretion, and, when consumed excessively, can promote ulcer development. Alcohol consumption increases the risk of bleeding in patients with peptic ulcer disease (Lee 2013; Chai 2011; Kuipers 2012). Alcohol consumption should be avoided by people who have ulcers and those at high risk for developing ulcers.

Stress Management

Psychological stress and tension is correlated with gastric and duodenal ulcers (Cheng 2000). In a study in 47 patients with peptic ulcer disease, an integrated stress management program involving seven one-hour sessions over four weeks was compared with listening to a relaxation tape. Over four months of follow-up, those who participated in the stress management program had greater relief of stress symptoms and better ulcer healing than those who only listened to the relaxation tapes (Han 2002). A number of techniques for reducing stress are described in the Stress Management protocol.

9 Integrative Interventions

Primary Support

Licorice and DGL. Licorice (Glycyrrhiza glabra) root has been used for centuries to treat a wide array of health problems, including peptic ulcers. Deglycyrrhizinated licorice, or DGL, is made by removing a component of licorice that has been associated with side effects such as fluid retention and high blood pressure (Shibata 2000; Borrelli 2000; UMMC 2016).

In a randomized, double-blind, placebo-controlled trial, 100 patients who tested positive for H. pylori were treated with 150 mg per day of a DGL preparation or placebo for 30 days. At the end of the treatment period, 56% of the DGL group and 4% of the placebo group tested negative for H. pylori (Puram 2013). The addition of licorice to standard treatment of H. pylori-positive ulcers has also been shown to be beneficial. In a randomized controlled trial, licorice extract improved the H. pylori eradication rate of standard triple therapy (the combination of two antibiotics plus a proton pump inhibitor [PPI]) (Hajiaghamohammadi 2016), while another controlled clinical trial found that triple therapy plus licorice extract was as effective as bismuth quadruple therapy (Momeni 2014).

Licorice root, DGL, and combinations of DGL and antacids have been studied for decades for the treatment of peptic ulcers, with many of these trials finding a positive therapeutic effect (Tewari 1968; Turpie 1969). One trial using a combination product of DGL plus antacids found this preparation to be nearly as effective as cimetidine in reducing recurrence of stomach ulcers over a two-year period (Morgan 1985). In a clinical trial, concurrent administration of DGL and aspirin significantly reduced aspirin-induced bleeding, as measured by fecal blood loss (Rees 1979).

In a rat model, the incidence of aspirin-induced ulcers was reduced by half when the aspirin was coated with different forms of licorice, including DGL (Dehpour 1994). In other animal research, a DGL preparation reduced gastric acidity and decreased ulceration due to NSAID exposure and stress (Mukherjee 2010), and both licorice root extract and omeprazole (Prilosec, a PPI) were effective in preventing NSAID-induced ulcers (Jalilzadeh-Amin 2015).

Licorice compounds present in DGL have demonstrated anti-inflammatory, free radical-scavenging, and anti-ulcer activities in preclinical research (Choi 2015; Mukherjee 2010). DGL has also been shown to increase the number of mucous-producing cells and enhance mucous secretion in the rat stomach (van Marle 1981). Animal and laboratory studies confirm that compounds in licorice and DGL have activity against H. pylori, including antibiotic-resistant strains (Kim 2013; Krausse 2004; Fukai 2002; Wittschier 2009).

Zinc-carnosine. Zinc-carnosine, also called polaprezinc, is a combination of the mineral zinc and L-carnosine, a compound composed of the amino acids beta-alanine and L-histidine. Zinc-carnosine is thought to help protect the gastrointestinal lining (Watari 2013; Mahmood 2007).

In a randomized clinical trial in 66 participants with symptomatic H. pylori infection, zinc-carnosine significantly improved the ability of standard triple therapy (two antibiotics plus a proton pump inhibitor) to eradicate H. pylori. In those who completed treatment, 86% treated with triple therapy alone achieved eradication while 100% treated with triple therapy plus zinc-carnosine (150 mg twice daily) were H. pylori-negative four weeks after treatment (Kashimura 1999). In 20 patients with injury to the small intestine caused by low-dose aspirin, treatment with 150 mg per day of zinc-carnosine for four weeks resulted in a significant reduction in mucosal injury and ulcers compared with no treatment (Watari 2013). In another trial, 10 healthy individuals were treated for seven days with 37.5 mg twice per day of zinc-carnosine, or placebo. During the final five days, study subjects also consumed the NSAID indomethacin (Indocin, Tivorbex). Those who received placebo experienced a three-fold increase in intestinal permeability (a sign of mucosal damage), while those treated with zinc-carnosine did not have a significant increase in gut permeability (Mahmood 2007).

Studies using animal models of gastrointestinal mucosal damage have also demonstrated the cell-protective and anti-ulcer effects of zinc-carnosine (Choi 2013; Cho 1991; Seiki 1990). Among zinc-carnosine’s possible mechanisms of action are a reduction in inflammation, neutralizing tissue-damaging free radicals, preventing intestinal cell death, and protecting the tight junctions that link mucosal cells together (Watari 2013; Choi 2013).

Probiotics. Probiotics are microorganisms that confer health benefits when ingested (Lesbros-Pantoflickova 2007). Lactobacillus species, commonly used in probiotics, have been shown in laboratory studies to inhibit the growth of H. pylori and reduce H. pylori-associated inflammation (Enany 2015), and numerous randomized controlled trials have found that the addition of probiotics to standard antibiotic therapy markedly improves the success of H. pylori eradication (Boltin 2016; Dang 2014; Ma 2015). In one randomized trial, probiotics combined with triple therapy (two antibiotics plus a PPI) was compared with triple therapy alone in patients with H. pylori-associated peptic ulcers. The addition of probiotics resulted in an H. pylori eradication rate over 24% higher, and a total treatment effectiveness rate over 13% higher, compared with triple therapy alone (Ma 2015).

An important potential benefit of probiotics is the reduction of antibiotic-associated side effects, particularly diarrhea (Boltin 2016). An analysis of randomized controlled trials determined that Saccharomyces boulardii, a probiotic yeast, decreased side effects of antibiotic treatment of H. pylori (Dang 2014).

Lactobacillus reuteri DSM17648 is a probiotic strain that specifically binds to H. pylori bacteria in the gut, preventing them from adhering to the gastric mucosa and reducing their numbers in the stomach. L. reuteri DSM17648 supplements have been shown to decrease the H. pylori load in healthy H. pylori-positive individuals, and may thus prevent future H. pylori-associated problems, including the need for antibiotic treatment. These clinical effects of L. reuteri DSM 17648 were also demonstrated by preparations in which the L. reuteri bacteria were killed by freeze-drying or spray-drying procedures (Holz 2015; Mehling 2013). Similarly, S. boulardii has been found to reduce gastric colonies of H. pylori in symptom-free H. pylori-positive subjects (Namkin 2016).

Lactoferrin. Lactoferrin is a component of milk (Vogel 2012). It has been the subject of numerous clinical trials investigating its ability to eradicate H. pylori. A meta-analysis examined five randomized controlled trials that evaluated whether lactoferrin treatment was effective for H. pylori eradication. A total of 682 subjects took part in these trials, 316 of whom received lactoferrin, with the remainder serving as controls. Those who received lactoferrin had more than 2.2-fold higher odds of eradication compared with controls (Sachdeva 2009).

A later review suggested a number of different mechanisms by which lactoferrin could have an anti-H. pylori effect, including a complementary action to antibiotics, inhibition of H. pylori growth, and a reduction in the rate of treatment side effects (Sachdeva 2014).

Flavonoids/polyphenols. Polyphenols, naturally occurring compounds present throughout the plant kingdom, are obtained in the diet mostly from fruits, vegetables, spices, grains, coffee, tea, and wine (Cardona 2013). Flavonoids make up the largest group of polyphenolic compounds. Evidence from numerous studies indicate polyphenols, including flavonoids, hold promise in the prevention and treatment of peptic ulcers (Farzaei 2015; Mota 2009). Extracts from tea, apples, pomegranate, and grape seed are especially good sources of polyphenols with possible anti-ulcer and anti-H. pylori activity (Farzaei 2015; Ankolekar 2011).

Curcumin, the principal active ingredient in the spice turmeric (Curcuma longa), is a flavonoid with strong free radical-scavenging, anti-inflammatory, and anti-bacterial properties. In particular, curcumin has been found to reduce symptoms in those with H. pylori-associated ulcers when used in combination with standard triple therapy (two antibiotics plus a PPI) (Khonche 2016; Di Mario 2007). Preclinical and animal studies have found that curcumin protects against NSAID-induced and stress-induced ulcers by increasing gastric blood flow, decreasing gastric acid secretion, protecting against mucosal injury, and reducing H. pylori-induced inflammatory tissue damage (Sharma 2012; Morsy 2013; Kim 2016; Santos 2015).

Quercetin is a flavonoid found in a wide variety of plants and plant foods (Suganthy 2016). Findings from animal studies suggest quercetin may help prevent and heal peptic ulcers (Suzuki 1998; Yan 2011; Zahorodnyi 2003). Quercetin’s antihistamine activity may reduce gastric acidity (Farzaei 2015; Kahraman 2003).

Additional Support

Cranberry. Cranberry (Vaccinium macrocarpon), a good source of anthocyanins and well known for its usefulness against urinary tract infections, has also demonstrated anti-H. pylori properties in preclinical, animal, and clinical models (NIH 2016; Matsushima 2008).

In a randomized controlled trial in a population at high risk for stomach cancer, 90 days of twice-daily consumption of cranberry juice was more effective than placebo at suppressing H. pylori infection (Zhang 2005). In another randomized controlled trial, the addition of cranberry juice to triple therapy (two antibiotics plus a PPI) markedly improved the rate of H. pylori eradication in women (Shmuely 2007).

In preclinical research, cranberry extract inhibited the growth and proliferation of H. pylori. This action was attributed to its polyphenol components (Matsushima 2008). A compound from cranberry has been shown to prevent H. pylori from attaching to stomach lining cells and to mucus (Burger 2002; Burger 2000).

Glutamine. Glutamine, the most abundant amino acid in the body, is a major metabolic fuel for cells of the intestinal lining and immune cells (Zuhl 2015; Lacey 1990). Preclinical, animal, and human studies have shown that glutamine supplementation can help repair the intestinal lining (Zuhl 2015; Wang 2016).

Glutamine supplementation may be beneficial in preventing injury due to H. pylori infection. In a study in mice infected with H. pylori, supplemental dietary glutamine protected the stomach mucosa by modulating the immune response to H. pylori and reducing inflammation (Hagen 2009). In another study, long-term supplementation with glutamine prevented cancerous change in gastric mucosa of H. pylori-infected gerbils (Amagase 2010).

Vitamin C. In multiple trials, vitamin C deficiency has been associated with peptic ulcer disease, gastritis, H. pylori infection, and bleeding from peptic ulcers (Aditi 2012). At least one author has proposed that vitamin C may help prevent reinfection in those who have been treated for H. pylori infection, based on experimental evidence that vitamin C inhibits growth and colonization of H. pylori (Pal 2011).

In a randomized controlled trial, the addition of oral vitamin C (500 mg per day) to bismuth quadruple therapy was compared with the same quadruple therapy alone. The addition of vitamin C resulted in a significantly higher H. pylori eradication rate (78% vs. 49%) (Zojaji 2009). In a randomized clinical trial in patients with H. pylori infection and chronic gastritis, high-dose vitamin C treatment (5 grams daily for four weeks) resulted in H. pylori eradication in 30% of patients (Jarosz 1998).

Magnesium. Magnesium salts are common ingredients in antacid formulations, but magnesium also appears to possess important anti-ulcer properties. In one animal study, rats were pre-treated with magnesium before administration of an NSAID (indomethacin) to induce ulcers. Compared with an untreated control group, the magnesium-treated rats had significantly reduced ulcer formation. The anti-ulcer effects of magnesium were attributed to its ability to decrease the number of acid-secreting cells and increase the number of mucous-producing cells in the stomach (Adewoye 2013).

Whey protein. In animal studies, whey and whey protein-derived compounds have demonstrated ulcer-protective properties (Castro 2010; Rosaneli 2004; Rosaneli 2002). These effects of whey protein may be related to its role in raising levels of glutathione, which shields the mucosal lining from free radical damage (Rosaneli 2002). Whey protein contains high levels of sulfur-containing amino acids such as cysteine, which is utilized in the synthesis of glutathione, a powerful scavenger of free radicals (Zavorsky 2007). Increased mucous production and lower plasma gastrin (an acid-stimulating hormone) may also help explain whey protein’s mucosal protection (Castro 2010).

Phospholipids. The prevalence of duodenal ulcers is higher in countries where the diet is based on refined plant foods such as milled rice and wheat. Conversely, the duodenal ulcer rate is lower in countries where staple foods consist of unrefined wheat, corn, soy, millet, and legumes. Experimental studies have determined that the lipid portion of these whole, unrefined foods (eg, oil from wheat germ or bran) protects the stomach and duodenal mucosa by increasing gastric mucous production and forming a protective barrier against stomach acid (Tovey 2015). Within the lipid portion, phospholipids have been identified as active components (Tovey 2015; Tovey 2013).

In a clinical trial, 204 subjects between 50 and 74 years old were given either aspirin (325 mg daily) or the same dose of aspirin complexed with phosphatidylcholine for seven days; those who received the phosphatidylcholine-aspirin complex had less evidence of gastric and duodenal mucosal damage and ulcers compared with those receiving aspirin alone (Cryer 2011). Animal studies suggest phospholipids may protect against the damaging effects of other NSAIDs such as naproxen and indomethacin as well (Tovey 2015).

Aloe vera extract. Aloe vera extracts have been shown to have healing and anti-inflammatory effects for skin damage, burns, pain, and edema. Preclinical and animal studies have found that Aloe vera also has gastroprotective and anti-ulcer properties (Keshavarzi 2014; Eamlamnam 2006).

In an early trial in 12 patients diagnosed with peptic ulcer disease, administration of a tablespoon of Aloe vera gel emulsion daily led to complete recovery (Blitz 1963). Results from animal studies indicate Aloe vera inhibits secretion of stomach acid (Keshavarzi 2014; Yusuf 2004), reduces gastric mucosal inflammation, and enhances stomach ulcer healing (Eamlamnam 2006; Park 2011). In a laboratory study, the inner gel of Aloe vera inhibited the growth of H. pylori bacteria, including antibiotic resistant strains (Cellini 2014).

Adewoye EO, Salami AT. Anti-ulcerogenic mechanism of magnesium in indomethacin induced gastric ulcer in rats. Nigerian journal of physiological sciences: official publication of the Physiological Society of Nigeria. 2013;28(2):193-199.

Aditi A, Graham DY. Vitamin C, gastritis, and gastric disease: a historical review and update. Digestive diseases and sciences. Oct 2012;57(10):2504-2515.

Allen A, Newton J, Oliver L, Jordan N, Strugala V, Pearson JP, Dettmar PW. Mucus and H. pylori. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society. Sep 1997;48(3):297-305.

Amagase K, Nakamura E, Endo T, Hayashi S, Hasumura M, Uneyama H, . . . Takeuchi K. New frontiers in gut nutrient sensor research: prophylactic effect of glutamine against Helicobacter pylori-induced gastric diseases in Mongolian gerbils. Journal of pharmacological sciences. 2010;112(1):25-32.

Amin M, Anwar F, Janjua MR, Iqbal MA, Rashid U. Green synthesis of silver nanoparticles through reduction with Solanum xanthocarpum L. berry extract: characterization, antimicrobial and urease inhibitory activities against Helicobacter pylori. International journal of molecular sciences. 2012;13(8):9923-9941.

Anand B. Medscape: Drugs & Diseases page. Peptic Ulcer Disease. http://emedicine.medscape.com/article/181753-overview. Last updated 1/29/2017.

Ankolekar C, Johnson D, Pinto Mda S, Johnson K, Labbe R, Shetty K. Inhibitory potential of tea polyphenolics and influence of extraction time against Helicobacter pylori and lack of inhibition of beneficial lactic acid bacteria. Journal of medicinal food. Nov 2011;14(11):1321-1329.

Antoniou T, Macdonald EM, Hollands S, Gomes T, Mamdani MM, Garg AX, . . . Juurlink DN. Proton pump inhibitors and the risk of acute kidney injury in older patients: a population-based cohort study. CMAJ open. Apr-Jun 2015;3(2):E166-171.

Atkinson NS, Reynolds DJ, Travis SP. 'Lemonade Legs': Why do Some Patients Get Profound Hypomagnesaemia on Proton-Pump Inhibitors? Intestinal research. Jul 2015;13(3):227-232.

Blaser MJ. Helicobacter pylori and gastric diseases. BMJ: British Medical Journal. 1998;316(7143):1507-1510.

Blaser MJ, Chen Y, Reibman J. Does Helicobacter pylori protect against asthma and allergy? Gut. 2008;57(5):561-567.

Blitz JJ, Smith JW, Gerard JR. Aloe vera gel in peptic ulcer therapy: preliminary report. J Am Osteopath Assoc. Apr 1963;62:731-735.

Boltin D. Probiotics in Helicobacter pylori-induced peptic ulcer disease. Best Pract Res Clin Gastroenterol. Feb 2016;30(1):99-109.

Borrelli F, Izzo AA. The plant kingdom as a source of anti-ulcer remedies. Phytotherapy Research. 2000;14(8):581-591.

Burger O, Ofek I, Tabak M, Weiss EI, Sharon N, Neeman I. A high molecular mass constituent of cranberry juice inhibits helicobacter pylori adhesion to human gastric mucus. FEMS immunology and medical microbiology. Dec 2000;29(4):295-301.

Burger O, Weiss E, Sharon N, Tabak M, Neeman I, Ofek I. Inhibition of Helicobacter pylori adhesion to human gastric mucus by a high-molecular-weight constituent of cranberry juice. Critical reviews in food science and nutrition. 2002;42(3 Suppl):279-284.

Cardona F, Andres-Lacueva C, Tulipani S, Tinahones FJ, Queipo-Ortuno MI. Benefits of polyphenols on gut microbiota and implications in human health. The Journal of nutritional biochemistry. Aug 2013;24(8):1415-1422.

Castro GA, Carvalho JE, Tinti SV, Possenti A, Sgarbieri VC. Anti-ulcerogenic effect of a whey protein isolate and collagen hydrolysates against ethanol ulcerative lesions on oral administration to rats. Journal of medicinal food. Feb 2010;13(1):83-90.

Castro M, Romero C, de Castro A, Vargas J, Medina E, Millan R, Brenes M. Assessment of Helicobacter pylori eradication by virgin olive oil. Helicobacter. Aug 2012;17(4):305-311.

CCF. The Cleveland Clinic Foundation. Peptic Ulcer Disease. https://my.clevelandclinic.org/health/articles/peptic-ulcer-disease. Copyright 2017. Accessed 6/20/2017.

Cellini L, Di Bartolomeo S, Di Campli E, Genovese S, Locatelli M, Di Giulio M. In vitro activity of Aloe vera inner gel against Helicobacter pylori strains. Lett Appl Microbiol. Jul 2014;59(1):43-48.

Chai J. Peptic Ulcer Disease. Rijeka, Croatia: InTech; 2011. Accessed 5/27/2016.

Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with asthma and allergy. Archives of internal medicine. Apr 23 2007;167(8):821-827.

Cheng Y, Macera CA, Davis DR, Blair SN. Does physical activity reduce the risk of developing peptic ulcers? British journal of sports medicine. Apr 2000;34(2):116-121.

Chey WD, Leontiadis GI, Howden CW, Moss SF. ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol. Feb 2017;112(2):212-239.

Cho CH, Luk CT, Ogle CW. The membrane-stabilizing action of zinc carnosine (Z-103) in stress-induced gastric ulceration in rats. Life sciences. 1991;49(23):Pl189-194.

Choi HS, Lim JY, Chun HJ, Lee M, Kim ES, Keum B, . . . Sul D. The effect of polaprezinc on gastric mucosal protection in rats with ethanol-induced gastric mucosal damage: comparison study with rebamipide. Life sciences. Jul 30 2013;93(2-3):69-77.

Choi YH, Kim YJ, Chae HS, Chin YW. In vivo gastroprotective effect along with pharmacokinetics, tissue distribution and metabolism of isoliquiritigenin in mice. Planta Med. May 2015;81(7):586-593.

Choi YJ, Kim N, Lee JY, Nam RH, Chang H, Seo JH, . . . Lee DH. Protective effects of garlic extract, PMK-S005, against nonsteroidal anti-inflammatory drugs-induced acute gastric damage in rats. Digestive diseases and sciences. Dec 2014;59(12):2927-2934.

CIHR. Canadian Institutes of Health Research. Drugbank: Misoprostol. https://www.drugbank.ca/drugs/DB00929. Last updated 6/11/2017. Accessed 6/12/2017.

Cope C. Base changes in the alkalosis produced by the treatment of gastric ulcer with alkalies. Clinical Science. 1936;2:287-300.

Cryer B, Bhatt DL, Lanza FL, Dong JF, Lichtenberger LM, Marathi UK. Low-dose aspirin-induced ulceration is attenuated by aspirin-phosphatidylcholine: a randomized clinical trial. Am J Gastroenterol. Feb 2011;106(2):272-277.

Dakal TC, Kumar A, Majumdar RS, Yadav V. Mechanistic Basis of Antimicrobial Actions of Silver Nanoparticles. Front Microbiol. 2016;7:1831.

Dang Y, Reinhardt JD, Zhou X, Zhang G. The effect of probiotics supplementation on Helicobacter pylori eradication rates and side effects during eradication therapy: a meta-analysis. PloS one. 2014;9(11):e111030.

Dehpour AR, Zolfaghari ME, Samadian T, Vahedi Y. The protective effect of liquorice components and their derivatives against gastric ulcer induced by aspirin in rats. The Journal of pharmacy and pharmacology. Feb 1994;46(2):148-149.

den Hoed CM, Vila AJ, Holster IL, Perez-Perez GI, Blaser MJ, de Jongste JC, Kuipers EJ. Helicobacter Pylori and the Birth Cohort Effect: Evidence for Stabilized Colonization Rates in Childhood. Helicobacter. 2011;16(5):405-409.

Di Mario F, Cavallaro LG, Nouvenne A, Stefani N, Cavestro GM, Iori V, . . . Franze A. A curcumin-based 1-week triple therapy for eradication of Helicobacter pylori infection: something to learn from failure? Helicobacter. Jun 2007;12(3):238-243.

Dial EJ, Lichtenberger LM. Milk protection against experimental ulcerogenesis in rats. Digestive diseases and sciences. Oct 1987;32(10):1145-1150.

Dial EJ, Romero JJ, Lichtenberger LM. Gastroprotection by dairy foods against stress-induced ulcerogenesis in rats. Digestive diseases and sciences. Nov 1995;40(11):2295-2299.

DiMarino M. Merck Manual. Professional Version. Drug Treatment of Gastric Acidity. http://www.merckmanuals.com/professional/gastrointestinal-disorders/gastritis-and-peptic-ulcer-disease/drug-treatment-of-gastric-acidity. 12/2016b. Accessed June 8, 2016.

DiMarino M. Merck Manual. Professional Version. Peptic Ulcer Disease. http://www.merckmanuals.com/professional/gastrointestinal-disorders/gastritis-and-peptic-ulcer-disease/peptic-ulcer-disease. 12/2016a. Accessed May 30, 2016.

Eamlamnam K, Patumraj S, Visedopas N, Thong-Ngam D. Effects of Aloe vera and sucralfate on gastric microcirculatory changes, cytokine levels and gastric ulcer healing in rats. World J Gastroenterol. Apr 7 2006;12(13):2034-2039.

Eastwood GL. The role of smoking in peptic ulcer disease. Journal of clinical gastroenterology. 1988;10 Suppl 1:S19-23.

Enany S, Abdalla S. In vitro antagonistic activity of Lactobacillus casei against Helicobacter pylori. Brazilian journal of microbiology: [publication of the Brazilian Society for Microbiology]. Oct-Dec 2015;46(4):1201-1206.

Farzaei MH, Abdollahi M, Rahimi R. Role of dietary polyphenols in the management of peptic ulcer. World J Gastroenterol. Jun 7 2015;21(21):6499-6517.

FDA. U.S. Food and Drug Administration. Drugs page. FDA Drug Safety Communication: Clostridium difficile-associated diarrhea can be associated with stomach acid drugs known as proton pump inhibitors (PPIs). http://www.fda.gov/drugs/drugsafety/ucm290510.htm. Last updated 1/19/2016a. Accessed 1/26/2016.

FDA. U.S. Food and Drug Administration. Drugs: FDA Drug Safety Communication: Low magnesium levels can be associated with long-term use of Proton Pump Inhibitor drugs (PPIs). https://www.fda.gov/Drugs/DrugSafety/ucm245011.htm. Last updated 4/7/2016b. Accessed 7/11/2017.

Ferri FF. Ferri's Clinical Advisor. Peptic Ulcer Disease. www.clinicalkey.com. Copyright 2016 Elsevier Inc. Accessed 6/30/2016.

Force RW, Nahata MC. Effect of histamine H2-receptor antagonists on vitamin B12 absorption. Ann Pharmacother. Oct 1992;26(10):1283-1286.

Fournier MR, Targownik LE, Leslie WD. Proton pump inhibitors, osteoporosis, and osteoporosis-related fractures. Maturitas. Sep 20 2009;64(1):9-13.

Freedberg DE, Lebwohl B, Abrams JA. The impact of proton pump inhibitors on the human gastrointestinal microbiome. Clinics in laboratory medicine. Dec 2014;34(4):771-785.

Fujimori S. What are the effects of proton pump inhibitors on the small intestine? World J Gastroenterol. Jun 14 2015;21(22):6817-6819.

Fukai T, Marumo A, Kaitou K, Kanda T, Terada S, Nomura T. Anti-Helicobacter pylori flavonoids from licorice extract. Life sciences. Aug 9 2002;71(12):1449-1463.

Fusaro M, Noale M, Tripepi G, Giannini S, D'Angelo A, Pica A, . . . Gallieni M. Long-term proton pump inhibitor use is associated with vascular calcification in chronic kidney disease: a cross-sectional study using propensity score analysis. Drug safety: an international journal of medical toxicology and drug experience. Aug 2013;36(8):635-642.

Giuliano C, Wilhelm SM, Kale-Pradhan PB. Are proton pump inhibitors associated with the development of community-acquired pneumonia? A meta-analysis. Expert Rev Clin Pharmacol. May 2012;5(3):337-344.

Gold Standard. Drug Monograph. Sucralfate. www.clinicalkey.com. Last updated 4/16/2013. Accessed 7/8/2016.

Graham DY. History of Helicobacter pylori, duodenal ulcer, gastric ulcer and gastric cancer. World J Gastroenterol. May 14 2014;20(18):5191-5204.

Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z. Proton pump inhibitor use, hip fracture, and change in bone mineral density in postmenopausal women: results from the Women's Health Initiative. Archives of internal medicine. May 10 2010;170(9):765-771.

Griffith RD, Simmons BJ, Yazdani Abyaneh MA, Bray FN, Falto-Aizpurua LA, Nouri K. Colloidal Silver: Dangerous and Readily Available. JAMA Dermatol. Jun 2015;151(6):667-668.

Hagen SJ, Ohtani M, Zhou JR, Taylor NS, Rickman BH, Blackburn GL, Fox JG. Inflammation and foveolar hyperplasia are reduced by supplemental dietary glutamine during Helicobacter pylori infection in mice. The Journal of nutrition. May 2009;139(5):912-918.

Hajiaghamohammadi AA, Zargar A, Oveisi S, Samimi R, Reisian S. To evaluate of the effect of adding licorice to the standard treatment regimen of Helicobacter pylori. The Brazilian journal of infectious diseases: an official publication of the Brazilian Society of Infectious Diseases. Sep 8 2016.

Han KS. The effect of an integrated stress management program on the psychologic and physiologic stress reactions of peptic ulcer in Korea. International journal of nursing studies. Jul 2002;39(5):539-548.

Herszenyi L, Juhasz M, Mihaly E, Tulassay Z. [Peptic ulcer disease and stress]. Orvosi hetilap. Aug 30 2015;156(35):1426-1429.

Ho SW, Hsieh MJ, Yang SF, Yeh YT, Wang YH, Yeh CB. Risk of Stroke-Associated Pneumonia With Acid-Suppressive Drugs: A Population-Based Cohort Study. Medicine. Jul 2015;94(29):e1227.

Holz C, Busjahn A, Mehling H, Arya S, Boettner M, Habibi H, Lang C. Significant Reduction in Helicobacter pylori Load in Humans with Non-viable Lactobacillus reuteri DSM17648: A Pilot Study. Probiotics Antimicrob Proteins. Jun 2015;7(2):91-100.

Homan M, Orel R. Are probiotics useful in Helicobacter pylori eradication? World J Gastroenterol. 2015;21(37):10644-10653.

IFFGD. International Foundation for Functional Gastrointestinal Disorders. Antacids. https://www.iffgd.org/diet-treatments/antacids.html. Last updated 9/4/2015. Accessed 6/12/2017.

JAGS. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. Nov 2015;63(11):2227-2246.

Jalilzadeh-Amin G, Najarnezhad V, Anassori E, Mostafavi M, Keshipour H. Antiulcer properties of Glycyrrhiza glabra L. extract on experimental models of gastric ulcer in mice. Iranian journal of pharmaceutical research: IJPR. Fall 2015;14(4):1163-1170.

Janarthanan S, Ditah I, Adler DG, Ehrinpreis MN. Clostridium difficile-associated diarrhea and proton pump inhibitor therapy: a meta-analysis. Am J Gastroenterol. Jul 2012;107(7):1001-1010.

Jarosz M, Dzieniszewski J, Dabrowska-Ufniarz E, Wartanowicz M, Ziemlanski S, Reed PI. Effects of high dose vitamin C treatment on Helicobacter pylori infection and total vitamin C concentration in gastric juice. European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP). Dec 1998;7(6):449-454.

Jung SW, Thamphiwatana S, Zhang L, Obonyo M. Mechanism of antibacterial activity of liposomal linolenic acid against Helicobacter pylori. PloS one. 2015;10(3):e0116519.

Kahraman A, Erkasap N, Koken T, Serteser M, Aktepe F, Erkasap S. The antioxidative and antihistaminic properties of quercetin in ethanol-induced gastric lesions. Toxicology. Feb 1 2003;183(1-3):133-142.

Kashimura H, Suzuki K, Hassan M, Ikezawa K, Sawahata T, Watanabe T, . . . Tanaka N. Polaprezinc, a mucosal protective agent, in combination with lansoprazole, amoxycillin and clarithromycin increases the cure rate of Helicobacter pylori infection. Alimentary pharmacology & therapeutics. Apr 1999;13(4):483-487.

Keshavarzi Z, Rezapour TM, Vatanchian M, Zare Hesari M, Nabizade Haghighi H, Izanlu M, . . . Shahveisi K. The effects of aqueous extract of Aloe vera leaves on the gastric acid secretion and brain and intestinal water content following acetic acid- induced gastric ulcer in male rats. Avicenna journal of phytomedicine. Mar 2014;4(2):137-143.

Khonche A, Biglarian O, Panahi Y, Valizadegan G, Soflaei SS, Ghamarchehreh ME, . . . Sahebkar A. Adjunctive Therapy with Curcumin for Peptic Ulcer: a Randomized Controlled Trial. Drug research. Aug 2016;66(8):444-448.

Kim JH, Jin S, Kwon HJ, Kim BW. Curcumin Blocks Naproxen-Induced Gastric Antral Ulcerations through Inhibition of Lipid Peroxidation and Activation of Enzymatic Scavengers in Rats. Journal of microbiology and biotechnology. Aug 28 2016;26(8):1392-1397.

Kim JM, Zheng HM, Lee BY, Lee WK, Lee DH. Anti-Helicobacter pylori Properties of GutGard. Preventive nutrition and food science. Jun 2013;18(2):104-110.

Klepser DG, Collier DS, Cochran GL. Proton pump inhibitors and acute kidney injury: a nested case-control study. BMC nephrology. 2013;14:150.

Krausse R, Bielenberg J, Blaschek W, Ullmann U. In vitro anti-Helicobacter pylori activity of Extractum liquiritiae, glycyrrhizin and its metabolites. The Journal of antimicrobial chemotherapy. Jul 2004;54(1):243-246.

Kuipers EJ, Blaser MJ, Goldman L (ed.), Schafer Ae. Goldman's Cecil Medicine, Twenty-Fourth Edition. Chapter 139: Acid Peptic Disease; 908-918e2. Copyright 2012 Saunders, an imprint of Elsevier, Inc. www.clinicalkey.com Accessed 6/30/2016.

Kuipers EJ BM. Goldman-Cecil Medicine. Acid Peptic Disease. 25 ed: Elsevier Health Sciences; 2015.

Kumar N, Kumar A, Broor SL, Vij JO, Anand BS. Effect of milk on patients with duodenal ulcers. British medical journal (Clinical research ed.). Sep 13 1986;293(6548):666.

Kuo CH, Lu CY, Yang YC, Chin C, Weng BC, Liu CJ, . . . Su HL. Does long-term use of silver nanoparticles have persistent inhibitory effect on H. pylori based on Mongolian gerbil's model? BioMed research international. 2014;2014:461034.

Kwok CS, Arthur AK, Anibueze CI, Singh S, Cavallazzi R, Loke YK. Risk of Clostridium difficile infection with acid suppressing drugs and antibiotics: meta-analysis. Am J Gastroenterol. Jul 2012;107(7):1011-1019.

Lacey JM, Wilmore DW. Is glutamine a conditionally essential amino acid? Nutrition reviews. Aug 1990;48(8):297-309.

Laine L, Nagar A. Long-Term PPI Use: Balancing Potential Harms and Documented Benefits. Am J Gastroenterol. Jul 2016;111(7):913-915.

Lambert AA, Lam JO, Paik JJ, Ugarte-Gil C, Drummond MB, Crowell TA. Risk of community-acquired pneumonia with outpatient proton-pump inhibitor therapy: a systematic review and meta-analysis. PloS one. 2015;10(6):e0128004.

Lau YT, Ahmed NN. Fracture risk and bone mineral density reduction associated with proton pump inhibitors. Pharmacotherapy. Jan 2012;32(1):67-79.

Lazarus B, Chen Y, Wilson FP, Sang Y, Chang AR, Coresh J, Grams ME. Proton Pump Inhibitor Use and the Risk of Chronic Kidney Disease. JAMA Intern Med. Jan 11 2016:238-246.

Lee L. First Consult. Peptic ulcer disease. www.clinicalkey.com. Last updated 1/15/2013. Accessed May 28, 2016.

Lesbros-Pantoflickova D, Corthesy-Theulaz I, Blum AL. Helicobacter pylori and probiotics. The Journal of nutrition. Mar 2007;137(3 Suppl 2):812s-818s.

Liju VB, Jeena K, Kuttan R. Gastroprotective activity of essential oils from turmeric and ginger. Journal of basic and clinical physiology and pharmacology. Jan 2015;26(1):95-103.

Linder L, Tamboue C, Clements JN. Drug-Induced Vitamin B12 Deficiency: A Focus on Proton Pump Inhibitors and Histamine-2 Antagonists. Journal of pharmacy practice. Aug 12 2016.

Lombardo L, Foti M, Ruggia O, Chiecchio A. Increased incidence of small intestinal bacterial overgrowth during proton pump inhibitor therapy. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. Jun 2010;8(6):504-508.

Ma F, Zhou C, Wang J, Liu T, Liu J. Probiotics in the treatment of peptic ulcer infected by helicobacter pylory and its safety. Pakistan journal of pharmaceutical sciences. May 2015;28(3 Suppl):1087-1090.

Maggio M, Corsonello A. Harmful effects of proton pump inhibitors: discrepancies between observational studies and randomized clinical trials--reply. JAMA internal medicine. Sep 9 2013;173(16):1559-1560.

Maggio M, Corsonello A, Ceda GP, Cattabiani C, Lauretani F, Butto V, . . . Lattanzio F. Proton pump inhibitors and risk of 1-year mortality and rehospitalization in older patients discharged from acute care hospitals. JAMA Intern Med. Apr 8 2013;173(7):518-523.

Mahady GB, Pendland SL, Yun G, Lu ZZ. Turmeric (Curcuma longa) and curcumin inhibit the growth of Helicobacter pylori, a group 1 carcinogen. Anticancer research. Nov-Dec 2002;22(6c):4179-4181.

Mahady GB, Pendland SL, Yun GS, Lu ZZ, Stoia A. Ginger (Zingiber officinale Roscoe) and the gingerols inhibit the growth of Cag A+ strains of Helicobacter pylori. Anticancer research. Sep-Oct 2003;23(5a):3699-3702.

Mahmood A, FitzGerald AJ, Marchbank T, Ntatsaki E, Murray D, Ghosh S, Playford RJ. Zinc carnosine, a health food supplement that stabilises small bowel integrity and stimulates gut repair processes. Gut. Feb 2007;56(2):168-175.

Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet. Oct 24 2009;374(9699):1449-1461.

Malfertheiner P, Selgrad M. Helicobacter pylori infection and current clinical areas of contention. Current opinion in gastroenterology. Nov 2010;26(6):618-623.

Matsushima M, Suzuki T, Masui A, Kasai K, Kouchi T, Takagi A, . . . Mine T. Growth inhibitory action of cranberry on Helicobacter pylori. Journal of gastroenterology and hepatology. Dec 2008;23 Suppl 2:S175-180.

McNeil C. Helicobacter pylori: good side complicates efforts to combat bad side. Journal of the National Cancer Institute. Dec 17 2008;100(24):1748-1750.

Medarov BI. Milk-Alkali Syndrome. Mayo Clinic proceedings. Mar 2009;84(3):261-267.

Mehling H, Busjahn A. Non-viable Lactobacillus reuteri DSMZ 17648 (Pylopass) as a new approach to Helicobacter pylori control in humans. Nutrients. Aug 2013;5(8):3062-3073.

Meyer MM. Epocrates [online database]. Monograph: Peptic ulcer disease. www.epocrates.com. Last updated 10/15/2015. Accessed 5/20/2016.

Miki K, Urita Y, Ishikawa F, Iino T, Shibahara-Sone H, Akahoshi R, . . . Yokokura T. Effect of Bifidobacterium bifidum fermented milk on Helicobacter pylori and serum pepsinogen levels in humans. J Dairy Sci. Jun 2007;90(6):2630-2640.

Milosavljevic T, Kostic-Milosavljevic M, Jovanovic I, Krstic M. Complications of peptic ulcer disease. Digestive diseases (Basel, Switzerland). 2011;29(5):491-493.

Momeni A, Rahimian G, Kiasi A, Amiri M, Kheiri S. Effect of licorice versus bismuth on eradication of Helicobacter pylori in patients with peptic ulcer disease. Pharmacognosy Res. Oct 2014;6(4):341-344.

Morgan AG, Pacsoo C, McAdam WA. Maintenance therapy: a two year comparison between Caved-S and cimetidine treatment in the prevention of symptomatic gastric ulcer recurrence. Gut. Jun 1985;26(6):599-602.

Morsy MA, El-Moselhy MA. Mechanisms of the protective effects of curcumin against indomethacin-induced gastric ulcer in rats. Pharmacology. 2013;91(5-6):267-274.

Mota KS, Dias GE, Pinto ME, Luiz-Ferreira A, Souza-Brito AR, Hiruma-Lima CA, . . . Batista LM. Flavonoids with gastroprotective activity. Molecules. 2009;14(3):979-1012.

Mukherjee M, Bhaskaran N, Srinath R, Shivaprasad HN, Allan JJ, Shekhar D, Agarwal A. Anti-ulcer and antioxidant activity of GutGard. Indian journal of experimental biology. Mar 2010;48(3):269-274.

Namkin K, Zardast M, Basirinejad F. Saccharomyces Boulardii in Helicobacter Pylori Eradication in Children: A Randomized Trial From Iran. Iranian journal of pediatrics. Feb 2016;26(1):e3768.

NCBI. National Center for Biotechnology Information. Bismuth Subsalicylate. https://pubchem.ncbi.nlm.nih.gov/compound/bismuth_subsalicylate#section=Top. 8/23/2007. Accessed 6/12/2017.

NIH. National Institutes of Health. National Center for Complementary and Integrative Health. https://nccih.nih.gov/health/silver#hed2. Last updated 4/2017. Accessed 7/20/2017.

NIH. NIH. National Center for Complementary and Integrative Health. Cranberry. https://nccih.nih.gov/health/cranberry. Last updated 11/2016. Accessed July 20, 2017.

NIH. NIH. National Institute of Diabetes and Digetsive and Kidney Diseases. Smoking and the Digestive System. http://www.niddk.nih.gov/health-information/health-topics/digestive-diseases/smoking/Pages/facts.aspx#peptic. 9/2013. Accessed June 15, 2016.

NLM. U.S. National Library of Medicine. Clostridium Difficile Infections. https://medlineplus.gov/clostridiumdifficileinfections.html. Last updated 6/13/2017a. Accessed 6/14/2017.

NLM. U.S. National Library of Medicine. H2 blockers. https://medlineplus.gov/ency/patientinstructions/000382.htm. Last updated 6/5/2017b. Accessed 6/12/2017.

Overmier JB, Murison R. Restoring psychology's role in peptic ulcer. Applied psychology. Health and well-being. Mar 2013;5(1):5-27.

Owyang SY, Luther J, Kao JY. Helicobacter pylori: beneficial for most? Expert review of gastroenterology & hepatology. Dec 2011;5(6):649-651.

Pal J, Sanal MG, Gopal GJ. Vitamin-C as anti-Helicobacter pylori agent: More prophylactic than curative- Critical review. Indian journal of pharmacology. Nov 2011;43(6):624-627.

Parasher G, Eastwood GL. Smoking and peptic ulcer in the Helicobacter pylori era. European journal of gastroenterology & hepatology. Aug 2000;12(8):843-853.

Park CH, Nam DY, Son HU, Lee SR, Lee HJ, Heo JC, . . . Lee SH. Polymer fraction of Aloe vera exhibits a protective activity on ethanol-induced gastric lesions. International journal of molecular medicine. Apr 2011;27(4):511-518.

Patel AM, Adeseun GA, Goldfarb S. Calcium-Alkali Syndrome in the Modern Era. Nutrients. 2013;5(12):4880-4893.

Puram S, Suh HC, Kim SU, Bethapudi B, Joseph JA, Agarwal A, Kudiganti V. Effect of GutGard in the Management of Helicobacter pylori: A Randomized Double Blind Placebo Controlled Study. Evidence-based complementary and alternative medicine: eCAM. 2013;2013:263805.

Ramakrishnan K, Salinas RC. Peptic ulcer disease. American family physician. Oct 1 2007;76(7):1005-1012.

Ramirez E, Cabanas R, Laserna LS, Fiandor A, Tong H, Prior N, . . . Quirce S. Proton pump inhibitors are associated with hypersensitivity reactions to drugs in hospitalized patients: a nested case-control in a retrospective cohort study. Clin Exp Allergy. Mar 2013;43(3):344-352.

Rees WD, Rhodes J, Wright JE, Stamford LF, Bennett A. Effect of deglycyrrhizinated liquorice on gastric mucosal damage by aspirin. Scandinavian journal of gastroenterology. 1979;14(5):605-607.

Romero C, Medina E, Vargas J, Brenes M, De Castro A. In vitro activity of olive oil polyphenols against Helicobacter pylori. Journal of agricultural and food chemistry. Feb 7 2007;55(3):680-686.

Rosaneli CF, Bighetti AE, Antonio MA, Carvalho JE, Sgarbieri VC. Efficacy of a whey protein concentrate on the inhibition of stomach ulcerative lesions caused by ethanol ingestion. Journal of medicinal food. Winter 2002;5(4):221-228.

Rosaneli CF, Bighetti AE, Antonio MA, Carvalho JE, Sgarbieri VC. Protective effect of bovine milk whey protein concentrate on the ulcerative lesions caused by subcutaneous administration of indomethacin. Journal of medicinal food. Fall 2004;7(3):309-314.

Ryan-Harshman M, Aldoori W. How diet and lifestyle affect duodenal ulcers. Review of the evidence. Canadian family physician Medecin de famille canadien. May 2004;50:727-732.

Sachar H, Vaidya K, Laine L. Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis. JAMA Intern Med. Nov 2014;174(11):1755-1762.

Sachdeva A, Nagpal J. Meta-analysis: efficacy of bovine lactoferrin in Helicobacter pylori eradication. Alimentary pharmacology & therapeutics. Apr 1 2009;29(7):720-730.

Sachdeva A, Rawat S, Nagpal J. Efficacy of fermented milk and whey proteins in Helicobacter pylori eradication: a review. World J Gastroenterol. Jan 21 2014;20(3):724-737.

Safavi M, Sabourian R, Foroumadi A. Treatment of Helicobacter pylori infection: Current and future insights. World journal of clinical cases. Jan 16 2016;4(1):5-19.

Santos AM, Lopes T, Oleastro M, Gato IV, Floch P, Benejat L, . . . Guerreiro AS. Curcumin inhibits gastric inflammation induced by Helicobacter pylori infection in a mouse model. Nutrients. Jan 2015;7(1):306-320.

Seiki M, Ueki S, Tanaka Y, Soeda M, Hori Y, Aita H, . . . Okabe S. [Studies on anti-ulcer effects of a new compound, zinc L-carnosine (Z-103)]. Nihon Yakurigaku Zasshi. May 1990;95(5):257-269.

Shah NH, LePendu P, Bauer-Mehren A, Ghebremariam YT, Iyer SV, Marcus J, . . . Leeper NJ. Proton Pump Inhibitor Usage and the Risk of Myocardial Infarction in the General Population. PloS one. 2015;10(6):e0124653.

Sharma AV, Ganguly K, Paul S, Maulik N, Swarnakar S. Curcumin heals indomethacin-induced gastric ulceration by stimulation of angiogenesis and restitution of collagen fibers via VEGF and MMP-2 mediated signaling. Antioxidants & redox signaling. Feb 15 2012;16(4):351-362.

Shibata S. A drug over the millennia: pharmacognosy, chemistry, and pharmacology of licorice. Yakugaku Zasshi. Oct 2000;120(10):849-862.

Shih CJ, Chen YT, Ou SM, Li SY, Chen TJ, Wang SJ. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. International journal of cardiology. Nov 15 2014;177(1):292-297.

Shmuely H, Yahav J, Samra Z, Chodick G, Koren R, Niv Y, Ofek I. Effect of cranberry juice on eradication of Helicobacter pylori in patients treated with antibiotics and a proton pump inhibitor. Molecular nutrition & food research. Jun 2007;51(6):746-751.

Sippy BW. Gastric and duodenal ulcer: Medical cure by an efficient removal of gastric juice corrosion. Journal of the American Medical Association. 1915;LXIV(20):1625-1630.

Suganthy N, Devi KP, Nabavi SF, Braidy N, Nabavi SM. Bioactive effects of quercetin in the central nervous system: Focusing on the mechanisms of actions. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. Dec 2016;84:892-908.

Suzuki Y, Ishihara M, Segami T, Ito M. Anti-ulcer effects of antioxidants, quercetin, alpha-tocopherol, nifedipine and tetracycline in rats. Japanese journal of pharmacology. Dec 1998;78(4):435-441.

Teramura-Gronblad M, Bell JS, Poysti MM, Strandberg TE, Laurila JV, Tilvis RS, . . . Pitkala KH. Risk of death associated with use of PPIs in three cohorts of institutionalized older people in Finland. Journal of the American Medical Directors Association. Jun 2012;13(5):488.e489-413.

Tewari SN, Trembalowicz FC. Some experience with deglycyrrhizinated liquorice in the treatment of gastric and duodenal ulcers with special reference to its spasmolytic effect. Gut. 1968;9(1):48-51.

Thamphiwatana S, Gao W, Obonyo M, Zhang L. In vivo treatment of Helicobacter pylori infection with liposomal linolenic acid reduces colonization and ameliorates inflammation. Proceedings of the National Academy of Sciences of the United States of America. Dec 9 2014;111(49):17600-17605.

Tovey FI. Role of dietary phospholipids and phytosterols in protection against peptic ulceration as shown by experiments on rats. World J Gastroenterol. Feb 7 2015;21(5):1377-1384.

Tovey FI, Bardhan KD, Hobsley M. Dietary phosphilipids and sterols protective against peptic ulceration. Phytotherapy research: PTR. Sep 2013;27(9):1265-1269.

Trikha A, Baillargeon JG, Kuo YF, Tan A, Pierson K, Sharma G, . . . Bonds RS. Development of food allergies in patients with gastroesophageal reflux disease treated with gastric acid suppressive medications. Pediatr Allergy Immunol. Sep 2013;24(6):582-588.

Turpie AG, Runcie J, Thomson TJ. Clinical trial of deglydyrrhizinized liquorice in gastric ulcer. Gut. 1969;10(4):299-302.

UMMC. University of Maryland Medical Center. Licorice Herb. Complementary and Alternative Medicine Guide. http://umm.edu/health/medical/altmed/herb/licorice. 2/2/2016. Accessed June 21, 2016.

UMMC. University of Maryland Medical Center. Peptic ulcer. http://www.umm.edu/health/medical/altmed/condition/peptic-ulcer. 10/19/2015. Accessed 6/20/2017.

UMMC. University of Maryland Medical Center. Peptic Ulcers. http://umm.edu/health/medical/reports/articles/peptic-ulcers. 10/2/2012. Accessed May 27, 2016.

Ushida Y, Shimokawa Y, Toida T, Matsui H, Takase M. Bovine alpha-lactalbumin stimulates mucus metabolism in gastric mucosa. J Dairy Sci. Feb 2007;90(2):541-546.

van Marle J, Aarsen PN, Lind A, van Weeren-Kramer J. Deglycyrrhizinised liquorice (DGL) and the renewal of rat stomach epithelium. European journal of pharmacology. Jun 19 1981;72(2-3):219-225.

Vogel HJ. Lactoferrin, a bird's eye view. Biochemistry and cell biology = Biochimie et biologie cellulaire. Jun 2012;90(3):233-244.

Waldum HL, Hauso O, Fossmark R. The regulation of gastric acid secretion - clinical perspectives. Acta physiologica (Oxford, England). Feb 2014;210(2):239-256.

Wang B, Wu Z, Ji Y, Sun K, Dai Z, Wu G. l-Glutamine Enhances Tight Junction Integrity by Activating CaMK Kinase 2-AMP-Activated Protein Kinase Signaling in Intestinal Porcine Epithelial Cells. The Journal of nutrition. Mar 2016;146(3):501-508.

Watari I, Oka S, Tanaka S, Aoyama T, Imagawa H, Shishido T, . . . Chayama K. Effectiveness of polaprezinc for low-dose aspirin-induced small-bowel mucosal injuries as evaluated by capsule endoscopy: a pilot randomized controlled study. BMC gastroenterology. 2013;13:108.

Wittschier N, Faller G, Hensel A. Aqueous extracts and polysaccharides from liquorice roots (Glycyrrhiza glabra L.) inhibit adhesion of Helicobacter pylori to human gastric mucosa. Journal of ethnopharmacology. Sep 7 2009;125(2):218-223.

Yan XM, Joo MJ, Lim JC, Whang WK, Sim SS, Im C, . . . Sohn UD. The effect of quercetin-3-O-beta-D-glucuronopyranoside on indomethacin-induced gastric damage in rats via induction of mucus secretion and down-regulation of ICAM-1 expression. Archives of pharmacal research. Sep 2011;34(9):1527-1534.

Yang Y-X. Chronic PPI Therapy and Calcium Metabolism. Curr Gastroenterol Rep. 2012;14(6):473-479.

Yaxley J, Chakravarty B. Helicobacter pylori eradication - an update on the latest therapies. Australian family physician. May 2014;43(5):301-305.

Yusuf S, Agunu A, Diana M. The effect of Aloe vera A. Berger (Liliaceae) on gastric acid secretion and acute gastric mucosal injury in rats. Journal of ethnopharmacology. Jul 2004;93(1):33-37.

Zaghlool SS, Shehata BA, Abo-Seif AA, Abd El-Latif HA. Protective effects of ginger and marshmallow extracts on indomethacin-induced peptic ulcer in rats. Journal of natural science, biology, and medicine. Jul-Dec 2015;6(2):421-428.

Zahorodnyi MI. [Effect of quercetin on sodium diclofenac-induced ulceration]. Likars'ka sprava / Ministerstvo okhorony zdorov'ia Ukrainy. Jan-Feb 2003(1):96-99.

Zavorsky GS, Kubow S, Grey V, Riverin V, Lands LC. An open-label dose-response study of lymphocyte glutathione levels in healthy men and women receiving pressurized whey protein isolate supplements. International journal of food sciences and nutrition. Sep 2007;58(6):429-436.

Zhang L, Ma J, Pan K, Go VL, Chen J, You WC. Efficacy of cranberry juice on Helicobacter pylori infection: a double-blind, randomized placebo-controlled trial. Helicobacter. Apr 2005;10(2):139-145.

Zojaji H, Talaie R, Mirsattari D, Haghazali M, Molaei M, Mohsenian N, . . . Zali MR. The efficacy of Helicobacter pylori eradication regimen with and without vitamin C supplementation. Dig Liver Dis. Sep 2009;41(9):644-647.

Zuhl M, Dokladny K, Mermier C, Schneider S, Salgado R, Moseley P. The effects of acute oral glutamine supplementation on exercise-induced gastrointestinal permeability and heat shock protein expression in peripheral blood mononuclear cells. Cell stress & chaperones. Jan 2015;20(1):85-93.