NATURAL APPROACHES FOR GASTROESOPHAGEAL REFLUX DISEASE AND RELATED DISORDERS Gastroesophageal reflux disease (GERD) is a chronic recurrent condition affecting millions ofAmericans. A recent study investigating the economic and social burden of gastrointestinal(GI) disease in the United States indicated that GERD was the most common GI-relateddiagnosis given at office visits in 2006. This study also showed that sales of proton pumpinhibitors (PPIs) exceeded $10 billion per year, and the number of prescriptions for PPIs peryear has doubled since 1999.1 Numerous environmental and genetic risk factors have beenimplicated in the pathogenesis of GERD. GERD commonly presents with heartburn and acidregurgitation, although there are numerous atypical presentations, such as chronic cough,noncardiac chest pain, laryngitis, and poor sleep quality. This disease is associated with severalother conditions, including Barrett's esophagus, esophageal carcinoma, gastritis, esophagitis,respiratory conditions, sleep disorders, and various ear-nose-throat (ENT) conditions. Con-ventional treatment often includes the use of PPIs and other acid blockers. Natural therapiesand lifestyle interventions are important to consider, owing to the chronic nature of GERD.
Studies attempting to assess the prevalence of GERD widely vary in their results, depending oncriteria used for diagnosis. A large survey performed by the National Heartburn Alliance in2000 estimated that 60 million Americans have GERD symptoms at least once per month, and25 million adults have daily symptoms. This survey revealed that 95% of these individualshave had symptoms for more than one year, and 54% have had symptoms for more than fiveyears. Forty percent of these individuals reported symptoms two to four times per week, and33% reported symptoms five times per week or more.2 This survey also showed that GERDsymptoms greatly affect activities of daily living, as more than 80% of the respondents reporteddecreased enjoyment of food, more than 60% reported that symptoms affected their ability tosleep well, and approximately 40% reported that their symptoms affect concentration at workand family activities.2 Both genetic and environmental factors appear to influence the presence of GERD. Numerousstudies have shown that obesity, weight gain, and increasing body mass index (BMI) areassociated with GERD. Hiatal hernia is also a risk factor for GERD symptoms. Studies indicatethat individuals with large hiatal hernias have shorter and weaker lower esophageal sphincters(LES), increased amount of reflux, less-efficient acid clearance, less-effective peristalsis, andincreased severity of esophagitis compared with individuals with small or no hiatal hernia.3Research also indicates that smoking, excess alcohol consumption, irritable bowel syndrome,and a family history of upper GI disease are risk factors. Pharmaceutical usage such as NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE anticholinergics, antidepressants, and inhaled bronchodilators are also related to the disease.
This study also associated lack of education and manual work with the presence of GERD.4 Additional studies have suggested that increased intake of table salt, sweets, or white bread is also a risk factor. Exercise and diets high in fruit and dietary fiber appear to be protectiveagainst the condition.5,6 However, high-intensity exercise has been shown to decrease LESpressure and induce GERD symptoms in otherwise asymptomatic individuals.7 Caffeine in-gestion also decreases LES pressure and decreases distal esophageal mean amplitude ofcontractions and peristaltic velocity, which can increase reflux.8 Ingestion of carbonated bev-erages has also been observed in a study to decrease the resting pressure, overall length, andabdominal length of the LES in healthy individuals temporarily. This study showed that 62% ofindividuals who drank carbonated beverages had significant decreases in these parameters tomeet the criteria for incompetence of the LES.9 GERD may present with atypical symptoms of esophageal and extraesophageal origin.
In addition, persistent wheezing, asthma, and airway hyper-responsiveness in childhood and adolescence have been shown to significantly increase risk for GERD symptoms at age 26independent of BMI.10 A study with a Spanish population indicated that long-term GERDsymptoms of 10 years or longer are associated with obesity and having a direct family memberwith GERD symptoms. GERD symptoms of 1 year or less were more closely correlated withhaving a spouse with GERD symptoms or taking 1–5 aspirins per week.11 Diagnosis of GERD is often based on symptoms. It is characterized by chronic intermittentheartburn as a burning sensation in the chest and throat as well as acid regurgitation presentingas a sensation of acid in the throat or mouth. GERD may also present with atypical symptomsof esophageal and extra-esophageal origin such as chronic cough, sleep disturbance, chest pain,asthma, and hoarseness.12 In fact, one study showed that 50% of individuals with noncardiacchest pain had abnormal pH tests or positive endoscopy confirming the presence of GERD.13 Apositive response to PPI therapy is frequently used to confirm the diagnosis of GERD. Ad-ditional diagnostic tests are performed for an individual with an atypical presentation, a highrisk for complications, or a poor response to initial therapy. Initially, a barium swallow andupper GI series are commonly performed. Esophageal pH monitoring is an important diag-nostic tool for GERD. Ambulatory pH monitoring detects abnormal levels of acid in theesophagus and can be used to correlate esophageal acid exposure with symptoms. The Bravocapsule is a wireless pH monitoring device that has been shown to be more tolerable, accurate,and sensitive than the catheter-based pH monitoring. The Bilitec system measures duodeno-gastroesophageal reflux by evaluating bilirubin absorbance; this system is useful particularlyfor the subset of patients that may be affected by duodenogastroesophageal reflux. Thesepatients report reflux symptoms with normal acid exposure in the esophagus on high-dose PPItherapy. Intraluminal impedance monitoring detects the composition, distribution, and clearingof both acid and nonacid esophageal reflux. Combined esophageal pH-impedance monitoring CLINICAL NATURAL MEDICINE HANDBOOK allows detection of nearly all gastroesophageal reflux episodes, acid as well as nonacid, whichprovides better diagnostics, particularly with patients on acid-suppression therapy.14 Esopha-geal manometry is also performed to measure the pressure at the LES. Esophagoscopy, morecommonly called endoscopy, is used to diagnose esophagitis, and a biopsy can differentiateesophageal strictures from cancer. Endoscopy should be performed on patients with chronicGERD symptoms to rule out Barrett's esophagus.
PATHOPHYSIOLOGY AND ASSOCIATED CONDITIONS Transient LES relaxation is the primary mechanism of GERD. It results from a vaso-vagalreflex triggered by stretch receptors of the proximal stomach. Studies have indicated that mostreflux episodes are acidic. However, according to one study, 28% of episodes were only weaklyacidic and 10% of episodes were weakly alkaline.15 Numerous factors may influence thesymptoms of GERD. Delayed gastric emptying, volume of gastric content, quantity and acidityof refluxed contents, ability of the esophagus to clear this material, LES function, and theresistance of the esophageal tissue can influence reflux symptoms.16 Some researchers haveproposed that patients with GERD can be categorized further as having erosive esophagitis,nonerosive reflux disease, and Barrett's esophagus.17 There is conflicting evidence regarding the role that Helicobacter pylori may play in GERDpathology. There are various studies that have looked at treatment of gastritis by eradicating H.
pylori and the effects of treatment on concurrent GERD symptoms. The results of these studiesvary from showing improvement to showing worsening of GERD symptoms.18 Researchregarding inflammation in the gastroesophageal junction, or cardia, has indicated that thepresence of erosive GERD or H. pylori gastritis is associated with the inflammation.19 Inaddition, GERD and carditis are associated with intestinal metaplasia at the gastroesophagealjunction.20 Esophagitis is common with GERD and may be classified as erosive or nonerosive with theseverity based on the number and location of mucosal breaks. Other types of esophagitis, suchas eosinophilic esophagitis, present with similar symptoms as GERD and are commonlymisdiagnosed. The common presentation of eosinophilic esophagitis is dysphagia and foodimpaction. Additional symptoms may include epigastric pain, emesis, weight loss, and failureto thrive.21 The diagnosis is based on a histologic finding of greater than 20 eosinophils perhigh-powered field in the esophageal squamous mucosa. This condition also presents withmotor disturbances that may cause food impaction in the absence of strictures. Manometryshows high amplitude long-duration waves in the distal esophagus particularly at night. Thesymptoms often respond to elimination or elemental dietary regimens and antiallergy treat-ment.22 Standard skin-prick tests measure type 1 hypersensitivity reactions, which are typicallymediated by immunoglobulin E (IgE). (It is possible to have a positive skin test but normalblood levels of IgE on a radioallergosorbent test [RAST].) However, these tests do notdiagnose many food-allergy reactions, which are frequently IgG-mediated. Thus, IgG testingcan offer additional insights that are frequently missed with standard skin-prick tests.
NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE Respiratory Conditions GERD is associated with numerous respiratory conditions. Approximately 10% of patientspresenting to ENT specialists have conditions that may be attributed to GERD.23 One studyrevealed that GERD is present in 75% of individuals with refractory ENT symptoms, and PPItherapy provided symptom relief or reduction in the majority of these individuals.24 Asthma isassociated with the presence of GERD symptoms, and although the relationship has not beenwell-studied. It is estimated that prevalence of GERD in people with asthma is between 60%–80% in adults and 50%–60% in children. Although the direct correlation is unknown, re-searchers have suggested that reflux aggravates asthma, which in turn induces further reflux.25GERD is associated with a chronic nonproductive cough in some individuals; the cough occursprimarily during the day and while these patients are in an upright position. One study dem-onstrated that chronic cough was caused by reflux in 21% of cases. In addition, the researchersshowed that chronic cough was the sole presenting symptom in GERD 43% of the time.26 Otitis media may also be linked to GERD.27 A study examining otitis media with effusion in adults demonstrated that pepsinogen concentration was higher in middle-ear effusion in patientswho reported GERD symptoms. In addition, treatment for GERD with PPIs provided somepatients with GERD symptom relief as well as decreasing the concentration of pepsinogen in theeffusion. Additionally, research has indicated that patients with chronic rhinosinusitis have anincreased prevalence of GERD. These chronic rhinosinusitis symptoms in many patients arereduced when their GERD is treated.28 Laryngeal symptoms may be associated with GERD.
Often, they present as hoarseness, frequent throat clearing, a postnasal drip, excess phlegm, sorethroat, dysphagia, a globus sensation, or cough. Chronic laryngitis and chronic sore throat areassociated with GERD in as many as 60% of patients.29 In addition, one study showed that atleast 50% of patients presenting with laryngeal and voice disorders had laryngopharyngeal re-flux.30 Less-common GERD-related laryngopharyngeal disorders include paroxysmal laryngos-pasm, subglottic stenosis, vocal-cord granuloma, and laryngeal and pharyngeal carcinoma.31 GERD has been shown to affect overall oral health. One study showed that children withGERD have increased dental erosion, salivary yeast, and salivary Mutans streptococci com-pared with healthy children.32 In addition, research indicates that children with GERD havemore dental caries and more severe erosion compared with healthy children.33 Sleep disturbance is common in individuals with GERD. Patients with obstructive sleep apnea(OSA) have GERD symptoms significantly higher than the general population.34 Studies haveindicated that the severity of GERD symptoms is correlated positively to the severity of OSA.35One study showed that treatment with continuous positive airway pressure (CPAP) in indi-viduals with GERD and OSA reduced supine esophageal-acid contact time to within normallevels in 81% of the study patients.36 In addition, researchers have shown that treatment ofGERD in patients who have OSA decreases the number of arousals during sleep.37 Barrett's Esophagus and Cancer Barrett's esophagus is a precancerous condition showing intestinal metaplasia of the loweresophagus and mucosecretory cells on histologic examination. It is the precursor to esophageal CLINICAL NATURAL MEDICINE HANDBOOK adenocarcinoma. Approximately 8%–10% of individuals with GERD have Barrett's esopha-gus.38 In fact, the cancer risk for an individual with Barrett's esophagus is 30 times higher thanin the general population. Risk factors for Barrett's esophagus include GERD for at least fiveyears' duration, male gender, Caucasian race, and age over 50.39 A study with U.S. veteransshowed that GERD increases the risk of both laryngeal and pharyngeal cancers independentfrom other risk factors.40 CONVENTIONAL TREATMENT Pharmaceutical acid blockers are usually the initial recommendation for both diagnosis andtreatment. Treatment recommendations are usually based on a step-up or step-down approachdepending on the severity of symptoms. Step-up treatment typically involves an eight-weektrial of a histamine H2-receptor antagonist taken two times per day as needed, changing to a PPIif symptoms are not controlled. The step-down approach begins with an eight-week trial of aPPI taken 30 to 60 minutes before the first meal of the day and then decreasing to the lowestpossible dosage that provides relief. Studies have indicated that both PPI therapy and H2blockers provide symptom relief for the majority of patients. One study showed that eightweeks of therapy with the PPI omeprazole relieved symptoms in 74%, and eight weeks of theH2 blocker ranitidine relieved symptoms in 50% of individuals with reflux esophagitis.41 Low-dose antacids have also been shown to decrease reflux symptoms better than a placebo.42 Long-term therapy with acid blockers has not been well-studied. Some research has indi- cated that nutrient deficiencies may arise with these treatments. Research has also suggestedthat long-term therapy with both PPI and H2 blockers increases the risk of vitamin B12 defi-ciency significantly in elderly adults.43 In fact, one study demonstrated that therapy with H2blockers caused a 53% decrease in absorption of protein-bound vitamin B12.44 H2 blockershave also been associated with decreased absorption of folic acid, iron, and zinc.45– 47 Researchhas demonstrated that treatment with the H2 blocker cimetidine significantly decreases intes-tinal calcium transport as well as altering vitamin D metabolism.48,49 There is also evidencethat long-term use of PPIs increases the risk of hip fracture significantly.50 Baclofen is a gamma-aminobutyric acid (GABA) receptor B agonist currently being in- vestigated as a possible treatment for GERD symptoms. Studies have indicated that baclofenreduces the rate of transient LES relaxations significantly, reduces the rate of gastroesophagealacid-reflux episodes, increases basal LES pressure, and increases gastric pH. Studies have alsosuggested that the drug is well-tolerated by patients.51 Atropine has also been studied as a Commonly Prescribed Pharmaceuticals for GERD Histamine H2-receptor antagonists Proton pump inhibitors Cimetidine (Tagamet) Lansoprazole (Prevacid) Famotidine (Pepcid) Esomeprazole (Nexium) Ranitidine (Zantac) Omeprazole (Prilosec) Nizatidine (Axid) Pantoprazole (Protonix)Rabeprazole (Aciphex) NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE treatment for GERD symptoms. Evidence suggests that administration of atropine decreasestransient relaxation in the LES and significantly decreases the number of reflux episodes.52However, atropine can only be administered short-term, via intramuscular injections or in-travenously.
Surgery is considered based on severity of disease, response to pharmaceutical treatment, riskof complications, and individual patient needs. The most frequent antireflux procedure per-formed is laparoscopic fundoplication, although surgery can also be done to correct hiatalhernias and other anatomical causes of GERD. Laparoscopic fundoplication places a gastricwrap around the gastroesophageal junction, strengthening the barrier function. Research hasindicated that fundoplication relieves heartburn and typical symptoms in 93% of patients, yetonly 56% of individuals had relief of their atypical symptoms.53 This procedure does notappear to replace the use of acid-blocking medication or decrease the incidence of carcinomaover standard medication therapy.54 Lifestyle Modification Lifestyle modifications can have a great impact on GERD symptoms. Diet recommendationsinclude avoiding foods that trigger symptoms. Common culprits include acidic foods, such astomatoes, coffee, tea, and citrus foods. Additionally, avoidance of foods that decrease LESpressure, such as high-fat foods, chocolate, peppermint, and alcohol, may be necessary. Re-search has shown that diets high in the antioxidant vitamin C are associated with less risk ofGERD symptoms, Barrett's esophagus, and esophageal adenocarcinoma.55 In addition, a smallstudy showed that very-low-carbohydrate diets reduce GERD symptoms and decrease loweresophageal acid exposure in obese individuals with GERD. In fact, this study showed that dietscontaining less than 20 g of carbohydrates per day significantly reduced symptoms in less thansix days.56 Another study demonstrated that chewing sugar-free gum for one half-hour after ameal reduced postprandial esophageal reflux possibly by increasing the frequency of swal-lowing.57 A study with children who had GERD symptoms that were unresponsive to treatmentshowed that feeding an elemental formula reduced or resolved all patients' GERD symptomsas well as improving histologic changes in the esophagus.58 Commonly, it is suggested topatients to sleep with the head of the bed elevated as well as sleeping in the left-lateraldecubitus position.59 Numerous studies have investigated the effect of weight loss on GERDsymptoms. Research has indicated that weight loss and decreased visceral fat mass correlatedsignificantly with decreased esophageal-acid exposure.60 Smoking cessation is also re-commended.
Alternative Supplements for Treating GERD Glycyrrhiza glabra (licorice) Digestive enzymes Atropa belladonna (belladonna) CLINICAL NATURAL MEDICINE HANDBOOK ALTERNATIVE TREATMENT Antioxidants have been shown to be protective in numerous diseases, such as GERD, gastriculcers, and GI cancers. Oxidative stress of the esophageal mucosa is a contributing factor in thepathology of GERD. A study was performed with individuals with both erosive and nonerosiveGERD pre- and post-antireflux surgery measuring oxidative stress. This study showed thatindividuals with GERD have lower glutathione levels in the distal esophagus compared withcontrols. In addition, myeloperoxidase activity in the distal esophagus decreased after anti-reflux surgery but never returned to levels found in the control group.61 Supplementation toincrease glutathione levels with the precursors N-acetyl-cysteine and selenium may be bene-ficial. Additional studies have shown that oxygen-free radicals measured by arachidonic acidperoxidation metabolites are significantly higher in patients with GERD compared with con-trols.62 Studies have also indicated that free-radical oxidative damage plays a role in gastricand duodenal ulcers as well in as gastric carcinoma.63 Although studies directly supporting antioxidant supplementation with GERD are lacking, substantial evidence supports using antioxidant therapy for patients with gastric ulcers andcancer, and shows that the therapy may also provide benefit for patients who have GERD.
Research has shown that the hormone and potent antioxidant melatonin prevented gastriculceration and reduced endogenous hydroxyl radicals by 88%. In fact, melatonin was shown tobe more effective than ranitidine for preventing stress-related ulcers in animal models.64 Fish oil supplementation has also been shown to protect gastric mucosa and decrease the severity of gastric ulceration in animal studies. Fish oil increased antioxidant enzyme activity,decreased acid-pepsin secretion, increased mucin secretion, and decreased lipid peroxidation inthe gastric mucosa.65 A study was performed with an antioxidant dietary supplement containing melatonin, L- tryptophan, vitamin B6, folic acid, vitamin B12, methionine, and betaine. The supplement oromeprazole was given to individuals with GERD. In this study, 100% of individuals who tookthe supplement had complete regression of their GERD symptoms within 40 days comparedwith less than 66% of individuals who had regression of symptoms treated with omeprazole.66 D-limonene is a monoterpene in citrus oil. Numerous studies have shown that D-limoneneexerts anti-cancer, antimicrobial, and anti-inflammatory effects. In particular, studies haveshown that this constituent of citrus oil is protective against GI cancers, including cancers of thestomach and colon, decreasing both growth and metastasis.67 Although direct evidence of D-limonene's effects on esophageal cancer is lacking, it is certainly possible that this monoter-pene may be protective against Barrett's esophagus and esophageal adenocarcinoma. Alter-native practitioners often recommend D-limonene for treatment of GERD with generally goodresults, although studies are lacking.
Glycyrrhiza glabra (licorice) root has historically been used as a demulcent and anti-inflam-matory botanical for treating conditions such as gastric and duodenal ulcers. Studies haveshown that ingestion of deglycyrrhizinated licorice (DGL) may increase mucous production NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE Tell Your Patients Lifestyle Modifications for GERD Lose weight.
 Avoid eating large meals.
 Avoid consuming acidic foods, such as citrus foods, tomatoes, coffee, and tea.
 Avoid caffeine and chocolate.
 Avoid consuming food allergens.
 Eat a diet high in fiber and antioxidants.
 Eat a low-carbohydrate diet.
 Avoid pharmaceuticals that aggravate GERD.
 Elevate the head of the bed 4–8 inches.
 Sleep in left-lateral decubitus (lying down) position.
 Avoid lying down 2–3 hours after a meal.
 Stop smoking.
and accelerate healing of duodenal and gastric ulcers.68,69 In addition, a small study showedthat DGL also accelerates healing of aphthous ulcers.70 Although studies that correlate DGLwith GERD directly are lacking, it is reasonable to assume that DGL may provide symptomrelief in patients with GERD. Clinically, alternative health care providers often prescribeadditional demulcent herbs for their healing and soothing properties, including such herbs asAloe vera (aloe), Ulmus fulva (slippery elm), and Althaea officinalis (marshmallow).
Pistacia lentiscus (mastic) resin is used medicinally for treating duodenal and gastric ulcers.
Animal studies show that it decreased H. pylori colonies thirtyfold.71 Research has also in-dicated that mastic resin oral supplementation protects gastric mucosa from experimentallyinduced damage as well as decreasing free acidity.72 In addition, a small study showed thatmastic supplementation provided symptomatic relief of duodenal ulcers in 80% of individualswho were treated with the supplement, and 70% experienced healing with endoscopy.73 Theantisecretory and cytoprotective activity of mastic may provide benefit for individuals withGERD, although direct evidence is lacking.
Calcium carbonate, magnesium, aluminum, and phosphate salts are frequently used in over-the-counter antacids. Studies have indicated that antacids are effective for treating GERDsymptoms, reducing acid regurgitation, and relieving both daytime and nighttime heartburn.74Mineral supplementation, using calcium and magnesium, may reduce GERD symptoms, al-though direct evidence is lacking.
Digestive Enzymes Supplemental digestive enzymes may reduce GERD symptoms. Delayed gastric emptyingand a large volume of food in the stomach are associated with GERD symptoms, and CLINICAL NATURAL MEDICINE HANDBOOK Figure 18–1. Aloevera (aloe).
supplementation using digestive enzymes may reduce these factors. Digestive enzymes arecommonly included in combination products, including lipase, amylase, protease, maltase,lactase, sucrase, phytase, and cellulase. Clinically, some patients actually benefit from hy-drochloric acid and pepsin supplementation, including individuals who have low levels ofstomach acid and delayed gastric emptying.
ALLERGY TREATMENT Eosinophilic esophagitis is frequently misdiagnosed as GERD. Allergy treatment may beindicated in individuals who are not responsive to typical GERD therapies. Allergy testing tomeasure both IgE and IgG antibodies is indicated. In addition, dietary supplementation, usingproducts to treat allergic reactions directly may also be necessary. Quercitin is a bioflavonoidoften used in allergies because it has antihistamine, anti-inflammatory, and antioxidant effects.
Vitamin C has been shown to be protective against GERD and to have antioxidant and someantihistamine properties.
Zinc carnosine has been shown to speed healing in many types of gastrointestinal lesions.
Many studies refer to polaprezinc, a chelate compound consisting of zinc and L-carnosine.
Studies show that polaprezinc has antioxidant activity and decreases the gastric inflammationcaused by H. pylori infection.75 Polaprezinc has been shown to protect gastric mucosa fromdamaging free radicals as well as speed healing of gastric lesions in animal models.76 Ad-ditionally, studies show that zinc carnosine improves intestinal integrity and decreased lab-induced gastric and small-intestine injury.77 L-Glutamine is an amino acid utilized as an energy source by intestinal epithelium. Researchhas shown that supplementation with glutamine prevented the development in chemical- NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE induced gastric lesions in stressed rats.78 Also, glutamine has been shown to decrease durationand severity of mucosal lesions induced by chemotherapy.79 Atropa belladonna (belladonna) is a botanical often used for its anticholinergic activity. One ofthe constituents of belladonna is atropine. Although anticholinergics have been shown toaggravate GERD, atropine has been shown to be beneficial. It is possible that belladonna maybe useful for treating GERD owing to the herb's atropine component.
GERD is a chronic recurring condition that makes a great impact on the quality of life ofindividuals who have this condition. As a result of the economic and social burdens of GERDin the United States, it is important for patients to have access to alternative therapies andlifestyle modifications. Currently, research in this area is minimal.
1Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J 2National Heartburn Alliance. Survey 2000 Results: A Community Perspective. 2000. Online document at: www.heartburnalliance.org/survey 2000.pdf. Accessed January 16, 2007.
3Patti MG, Goldberg HI, Arcerito M, et al. Hiatal hernia size affects lower esophageal sphincter function, esophageal acid exposure, and the degree of mucosal injury. Am J Surg. 1996;171:182–186.
4Mohammed I, Nightingale P, Trudgill NJ. Risk factors for gastro-oesophageal reflux disease symptoms: A community study. Aliment Pharmacol Ther. 2005;21:821–827.
5Nocon M, Labenz J, Willich SN. Lifestyle factors and symptoms of gastro-oesophageal reflux—a population-based study. Aliment Pharmacol Ther. 2006;23:169–174.
6Nilsson M, Johnsen R, Ye W, et al. Lifestyle related risk factors in the aetiology of gastro-oesophageal reflux. Gut. 2004;53:1730–1735.
7Maddison KJ, Shepherd KL, Hillman DR, Eastwood PR. Function of the lower esophageal sphincter during and after high-intensity exercise. Med Sci Sports Exerc. 2005;37:1728–1733.
8Lohsiriwat S, Puengna N, Leelakusolvong S. Effect of caffeine on lower esophageal sphincter pressure in Thai healthy volunteers. Dis Esophagus. 2006;19:183–188.
9Hamoui N, Lord RV, Hagen JA, et al. Response of the lower esophageal sphincter to gastric distention by carbonated beverages. J Gastrointest Surg. 2006;10:870–877.
10Hancox RJ, Poulton R, Taylor DR, et al. Associations between respiratory symptoms, lung function and gastro-oesophageal reflux symptoms in a population-based birth cohort. Respir Res. 2006;7:142.
11Diaz-Rubio M, Moreno-Elola-Olaso C, Rey E, et al. Symptoms of gastro-oesophageal reflux: Prevalence, severity, duration and associated factors in a Spanish population. Aliment Pharmacol Ther. 2004;19:95–105.
12Hungin AP, Raghunath AS, Wiklund I. Beyond heartburn: A systematic review of the extra-oesophageal spectrum of reflux-induced disease. Fam Pract. 2005;22:591–603.
13Dekel R, Martinez-Hawthorne SD, Guillen RJ, Fass R. Evaluation of symptom index in identifying gastroesophageal reflux disease–related noncardiac chest pain. J Clin Gastroenterol. 2004;38:24–29.
14Hirano I. Review article: Modern technology in the diagnosis of gastrooesophageal reflux disease—Bilitec, intraluminal impedance and Bravo capsule pH monitoring. Aliment Pharmacol Ther. 2006;23(suppl1):12–24.
15Zerbib F, des Varannes SB, Roman S, et al. Normal values and day-today variability of 24-h ambulatory oesophageal impedance-pH monitoring in a Belgian-French cohort of healthy subjects. Aliment PharmacolTher. 2005;22:1011–1021.
16Castell DO, Murray JA, Tutuian R, et al. Review article: The pathophysiology of gastro-oesophageal reflux disease—oesophageal manifestations. Aliment Pharmacol Ther. 2004;20(suppl9):14–25.
17Fass R, Ofman JJ. Gastroesophageal reflux disease—should we adopt a new conceptual framework? Am J Gastroenterol. 2002;97: 1901–1909.
CLINICAL NATURAL MEDICINE HANDBOOK 18Malfertheiner P, Peitz U. The interplay between Helicobacter pylori, gastrooesophageal reflux disease, and intestinal metaplasia. Gut. 2005;54(suppl.1):i13–i20.
19Voutilainen M, Farkkila M, Mecklin JP, et al. Chronic inflammation at the gastroesophageal junc- tion (carditis) appears to be a specific finding related to Helicobacter pylori infection and gastroesopha-geal reflux disease. The Central Finland Endoscopy Study Group. Am J Gastroenterol. 1999;94:3175–3180.
20Voutilainen M, Farkkila M, Juhola M, et al. Complete and incomplete intestinal metaplasia at the oesophagogastric junction: Prevalences and associations with endoscopic erosive oesophagitis and gastritis.
Gut. 1999;45:644–648.
21Pasha SF, Sharma VK, Crowell MD. Current concepts and treatment options in eosinophilic esophagitis.
Curr Opin Investig Drugs. 2006;7:992–996.
22Luis AL, Rinon C, Encinas JL, et al. Non stenotic food impaction due to eosinophilic esophagitis: A potential surgical emergency. Eur J Pediatr Surg. 2006;16:399– 402.
23Drug VL, Cobzeanu D, Papaghiuc C, et al. Gastroesophageal reflux involvement in ENT disorders [in Romanian]. Rev Med Chir Soc Med Nat Iasi. 2005;109:220–222.
24Poelmans J, Feenstra L, Tack J. Determinants of long-term outcome of patients with reflux-related ear, nose, and throat symptoms. Dig Dis Sci. 2006;51:282–288.
25Sontag SJ. Gastroesophageal reflux disease and asthma. J Clin Gastroenterol. 2000;30(3 suppl.):S9–S30.
26Irwin RS, Curley FJ, French CL. Chronic cough. Am Rev Respir Dis. 1990;141:640–647.
27Sone M, Yamamuro Y, Hayashi H, et al. Otitis media in adults as a symptom of gastroesophageal reflux.
Otolaryngol Head Neck Surg. 2007;136:19–22.
28Loehrl TA, Smith TL. Chronic sinusitis and gastroesophageal reflux: Are they related? Curr Opin Otolaryngol Head Neck Surg. 2004;12:18–20.
29Poelmans J, Tack J. Extraoesophageal manifestations of gastrooesophageal reflux. Gut. 2005;54:1492–1499.
30Koufman JA, Amin MR, Panetti M. Prevalence of reflux in 113 consecutive patients with laryngeal and voice disorders. Otolaryngol Head Neck Surg. 2000;123:385–388.
31Franco RA Jr. Laryngopharyngeal reflux. Allergy Asthma Proc. 2006;27:21–25.
32Ersin NK, Oncag O, Tumgor G, et al. Oral and dental manifestations of gastroesophageal reflux disease in children: A preliminary study. Pediatr Dent. 2006;28:279–284.
33Linnett V, Seow WK, Connor F, Shepherd R. Oral health of children with gastro-esophageal reflux disease: A controlled study. Aust Dent J. 2002;47:156–162.
34Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med.
35Demeter P, Visy KV, Magyar P. Correlation between severity of endoscopic findings and apnea- hypopnea index in patients with gastroesophageal reflux disease and obstructive sleep apnea. World JGastroenterol. 2005;11:839–841.
36Tawk M, Goodrich S, Kinasewitz G, Orr W. The effect of 1 week of continuous positive airway pressure treatment in obstructive sleep apnea patients with concomitant gastroesophageal reflux. Chest. 2006;130:1003–1008.
37Zanation AM, Senior BA. The relationship between extraesophageal reflux (EER) and obstructive sleep apnea (OSA). Sleep Med Rev. 2005;9:453– 458.
38Stoltey J, Reeba H, Ullah N, et al. Does Barrett's oesophagus develop over time in patients with chronic gastro-oesophageal reflux disease? Aliment Pharmacol Ther. 2007;25:83–91.
39Pascu O, Lencu M. Barrett's esophagus. Rom J Gastroenterol. 2004;13:219–222.
40El-Serag HB, Hepworth EJ, Lee P, Sonnenberg A. Gastroesophageal reflux disease is a risk factor for laryngeal and pharyngeal cancer. Am J Gastroenterol. 2001;96:2013–2018.
41Festen HP, Schenk E, Tan G, et al. Omeprazole versus high-dose ranitidine in mild gastroesophageal reflux disease: Short- and long-term treatment. The Dutch Reflux Study Group. Am J Gastroenterol.
42.Weberg R, Berstad A. Symptomatic effect of a low-dose antacid regimen in reflux oesophagitis. Scand J Gastroenterol. 1989;24:401– 406.
43Valuck RJ, Ruscin JM. A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol. 2004;57:422– 428.
44Salom IL, Silvis SE, Doscherholmen A. Effect of cimetidine on the absorption of vitamin B12. Scand J 45Russell RM, Golner BB, Krasinski SD, et al. Effect of antacid and H2 receptor antagonists on the intestinal absorption of folic acid. J Lab Clin Med. 1988;112:458– 463.
46Sturniolo GC, Montino MC, Rossetto L, et al. Inhibition of gastric acid secretion reduces zinc absorption in man. J Am Coll Nutr. 1991;10: 372–375.
47Aymard JP, Aymard B, Netter P, et al. Haematological adverse effects of histamine H2-receptor an- tagonists. Med Toxicol Adverse Drug Exp. 1988;3:430– 448.
NATURAL APPROACHES TO GASTROESOPHAGEAL REFLUX DISEASE 48Ghishan FK, Walker F, Meneely R, et al. Intestinal calcium transport: Effect of cimetidine. J Nutr.
49Odes HS, Fraser GM, Krugliak P, et al. Effect of cimetidine on hepatic vitamin D metabolism in humans.
50Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. 2006;296:2947–2953.
51Ciccaglione AF, Marzio L. Effect of acute and chronic administration of the GABA B agonist baclofen on 24 hour pH metry and symptoms in control subjects and in patients with gastro-oesophageal reflux disease.
Gut. 2003;52:464– 470.
52Lidums I, Checklin H, Mittal RK, Holloway RH. Effect of atropine on gastro-oesophageal reflux and transient lower oesophageal sphincter relaxations in patients with gastro-oesophageal reflux disease. Gut.
53So JB, Zeitels SM, Rattner DW. Outcomes of atypical symptoms attributed to gastroesophageal reflux treated by laparoscopic fundoplication. Surgery. 1998;124:28–32.
54Spechler SJ, Lee E, Ahnen D, et al. Long-term outcome of medical and surgical therapies for gastro- esophageal reflux disease: Follow-up of a randomized controlled trial. JAMA. 2001;285:2331–2338.
55Veugelers PJ, Porter GA, Guernsey DL, Casson AG. Obesity and lifestyle risk factors for gastro- esophageal reflux disease, Barrett esophagus and esophageal adenocarcinoma. Dis Esophagus. 2006;19:321–328.
56Austin GL, Thiny MT, Westman EC, et al. A very low–carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci. 2006;51:1307–1312.
57Moazzez R, Bartlett D, Anggiansah A. The effect of chewing sugarfree gum on gastro-esophageal reflux.
J Dent Res. 2005;84:1062–1065.
58Kelly KJ, Lazenby AJ, Rowe PC, et al. Eosinophilic esophagitis attributed to gastroesophageal reflux: Improvement with an amino acid-based formula. Gastroenterology. 1995;109:1503–1512.
59Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med. 2006;166:965–971.
60Mathus-Vliegen EM, Tygat GN. Gastro-oesophageal reflux in obese subjects: Influence of overweight, weight loss and chronic gastric balloon distension. Scand J Gastroenterol. 2002;37:1246–1252.
61Rantanen TK, Rasanen JV, Sihvo EI, et al. The impact of antireflux surgery on oxidative stress of esophageal mucosa caused by gastroesophageal reflux disease: 4-yr follow-up study. Am J Gastroenterol.
62Modzelewski B. Effect of arachidonic acid peroxidation products on the development of gastroesoph- ageal reflux disease [in Polish]. Pol Merkur Lekarski. 2004;16:532–535.
63Tandon R, Khanna HD, Dorababu M, Goel RK. Oxidative stress and antioxidants status in peptic ulcer and gastric carcinoma. Indian J Physiol Pharmacol. 2004;48:115–118.
64Bandyopadhyay D, Bandyopadhyay A, Das PK, Reiter RJ. Melatonin protects against gastric ulceration and increases the efficacy of ranitidine and omeprazole in reducing gastric damage. J Pineal Res. 2002;33:1–7.
65Bhattacharya A, Ghosal S, Bhattacharya SK. Effect of fish oil on offensive and defensive factors in gastric ulceration in rats. Prostaglandins Leukot Essent Fatty Acids. 2006;74:109–116.
66Pereira R de S. Regression of gastroesophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: Comparison with omeprazole. J Pineal Res. 2006;41:195–200.
67Lu XG, Zhan LB, Feng BA, et al. Inhibition of growth and metastasis of human gastric cancer implanted in nude mice by D-limonene. World J Gastroenterol. 2004;15;10:2140–2144.
68Larkworthy W, Holgate PF. Deglycyrrhizinized liquorice in the treatment of chronic duodenal ulcer: A retrospective endoscopic survey of 32 patients. Practitioner. 1975;215:787–792.
69Khayyal MT, el-Ghazaly MA, Kenawy SA, et al. Antiulcerogenic effect of some gastrointestinally acting plant extracts and their combination. Arzneimittelforschung. 2001;51:545–553.
70Das SK, Das V, Gulati AK, Singh VP. Deglycyrrhizinated liquorice in aphthous ulcers. J Assoc Physicians India. 1989;37:647.
71Paraschos S, Magiatis P, Mitakou S, et al. In vitro and in vivo activities of Chios mastic gum extracts and constituents against Helicobacter pylori. Antimicrob Agents Chemother. 2007;51:551–559.
72Al-Said MS, Ageel AM, Parmar NS, Tariq M. Evaluation of mastic, a crude drug obtained from Pistacia lentiscus for gastric and duodenal antiulcer activity. J Ethnopharmacol. 1986;15:271–278.
73Al-Habbal MJ, Al-Habbal Z, Huwez FU. A double-blind controlled clinical trial of mastic and placebo in the treatment of duodenal ulcer. Clin Exp Pharmacol Physiol. 1984;11:541–554.
74Weberg R, Berstad A. Symptomatic effect of a low-dose antacid regimen in reflux oesophagitis. Scand J Gastroenterol. 1989;24:401– 406.
CLINICAL NATURAL MEDICINE HANDBOOK 75Handa O, Yoshida N, Tanaka Y, Ueda M, Ishikawa T, Takagi T, Matsumoto N, Naito Y, Yoshikawa T.
Inhibitory effect of polaprezinc on the inflammatory response to Helicobacter pylori. Can J Gastroenterol.
2002 Nov;16(11):785–789.
76Nishiwaki H, Kato S, Sugamoto S, Umeda M, Morita H, Yoneta T, Takeuchi K. Ulcerogenic and healing impairing actions of monochloramine in rat stomachs: effects of zinc L-carnosine, polaprezinc. J PhysiolPharmacol. 1999 Jun;50(2):183–95.
77Mahmood 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. 2007Feb;56(2):168–175. Epub 2006 Jun 15.
78Anderson PM, Schroeder G, Skubitz KM. Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer. 1998 Oct 1;83(7):1433–1439.
79Okabe S, Hung CR, Takeuchi K, Takagi K. Effects of L-glutamine of acetylsalicylic acid or taurocholic acid-induced gastric lesions and secretory changes in pylorus-ligated rats under normal or stress conditions.
Jpn J Pharmacol. 1976 Aug;26(4):455– 460.

Source: http://www.liebertpub.com/dcontent/files/samplechapters/Sample_ClinicalNaturalMedicineHandbook.pdf

Tocotrienols, the vitamin e of the 21st century: its potential against cancer and other chronic diseases

Contents lists available at Biochemical Pharmacology Tocotrienols, the vitamin E of the 21st century: Its potential against cancer andother chronic diseases Bharat B. Aggarwal Chitra Sundaram, Seema Prasad, Ramaswamy Kannappan Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas, M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 143, Houston,TX 77030, USA


Alarm Solutions to the Worldwide Process and Power Industries Hazardous Area Notification ALARM ANNUNCIATORS SIL725 Safety Annunciator The SIL725 Safety Annunciator is designed and manufactured to provide As a world leading supplier of process alarm equipment, RTK Instruments will be a high safety integrity for critical alarm applications and for use as a