Gastroesophageal reflux disease (GERD): a review of conventional and alternative treatments

Study	n	Design	Length	Dosage	Indicators	Outcome
Young et al	29/30	DBRC in endoscopy-confirmed GERD; pyrogastrone vs. alginate raft	8 weeks	1 tid after meals and 2 at bedtime	Symptom rating scale, endoscopy	Pyrogastrone: 82% improvement in 8 weeks vs. 63% on antacid/alginate
Reed et al	37	DBRC in endoscopy-confirmed GERD; pyrogastrone vs. alginate raft	8 weeks	same	Symptom rating scale, endoscopy	Pyrogastrone:89% symptom remission in 8weeks; 95% endoscopyconfirmed esophageal ulcerremission compared with 67%controls (antacid/alginatealone)
Markham et al	104	Endoscopy confirmed GERD; Retrospective analysis in three groups: pyrogastrone, pyrogastrone plus metoclopramide, both with cimetidine	42 months	same	Symptom rating scale, endoscopy	Addition of either metoclopramide or cimetidine did not improve outcome; pyrogastrone alone resulted in symptom relief in 85% of 96 patients in 4-8 weeks; endoscopic healing in 76% of 55 patients in 4-8 weeks
Maxton et al	80	Endoscopy confirmed GERD;randomized to pyrogastrone or cimetidine	12 weeks	same	Symptom rating scale, endoscopy	Pyrogastrone: 40% healed at 6 weeks vs. 37% on cimetidine; both equivalent at 12 weeks

DBRC = double-blind, randomized, control trial

D-Limonene

D-limonene is found in citrus oils and used as a fragrance and favoring agent in body products and beverages. As such it is considered safe for ingestion and generally recognized as safe (GRAS). Clinical trials have determined no toxicity or side effects in humans at 100 mg/kg. In unpublished data, 19 patients with GERD or chronic heartburn were given 1,000 mg d-limonene daily or every other day. After 14 days, 89 percent of patients reported a complete remission of symptoms. Following this pilot trial, 13 participants with GERD or chronic heartburn were randomized to 1,000 mg d-limonene once daily or every other day or placebo. By day 4, 29 percent of participants on treatment experienced significant relief and by day 14, 86 percent experienced complete relief of all symptoms, compared to 29 percent on placebo. The mechanism of action of d-limonene in GERD and chronic heartburn is unknown, although in vitro research suggests it may protect mucosal surfaces from gastric acid and support normal peristalsis.

Esophagitis and Oxidant Stress

Because the severity of esophageal damage cannot be predicted based on the amount of time acid contacts the esophageal mucosa, nor can the pH of esophageal refluxate predict the severity of symptoms, researchers have proposed that factors other than the acidity of refluxate or the amount and duration of exposure to refluxate might determine esophageal damage. Several studies demonstrate mucosal resistance, infammation, and free radical damage are major determinants in the progression of reflux esophagitis.^120-122 The esophageal epithelium is morphologically and embryologically related to skin epithelium, and skin epithelium is recognized as a major immunological organ. The esophagus has similar keratinocytes and epithelial cells that are able to secrete proinfammatory cytokines (e.g., IL-8, IL-10, nuclear factor-kappaB [NF-kB], IL-6, and platelet adhesion factors). Esophageal biopsies demonstrate elevated levels of these cytokines in GERD, with signifcantly higher levels in Barrett's esophagus and adenocarcinoma than patients with erosive GERD.

Artemisia asiatica

Higher levels of reactive oxidant species are found in the esophageal tissue of patients with GERD, especially in Barrett's esophagus and esophageal adenocarcinoma. In an animal model, oxidative stress was found to be more important than acid exposure in development of esophageal ulcerations. In this animal model, the use of ethanol-extracted Artemisia asiatica, given at two dosages of 30 mg/kg or 100 mg/kg, acted as an antioxidant and was more efective in preventing esophageal erosion than ranitidine (Zantac®).

Curcumin, Quercetin, and Vitamin E

In a study designed to simulate acid exposure experienced by GERD patients, curcumin prevented the expression of infammatory cytokines in human esophageal tissue. In another animal model, rats with experimentally-induced reflux esophagitis were given quercetin (100 mg/kg) or alpha-tocopherol (16 IU/kg) and compared with rats on omeprazole. Both quercetin and alpha-tocopherol lowered the level of esophageal infammation and decreased acid and pepsin production in the stomach. Both antioxidants also raised levels of glutathione and other antioxidant enzymes while decreasing collagen production, indicating an antiinfammatory and antifibrotic effect.

Conclusion

Current conventional approaches to GERD management rely extensively on the use of PPIs. While these medications can be efective in treating non-erosive GERD, their utility for many GERD patients is less evidence-based. Over-reliance on PPIs is also potentially problematic because they are often used not only as a means of treating GERD, but as a means of diagnosis, with the response to a trial of a PPI routinely relied upon as the primary method of GERD diagnosis. If a patient responds favorably to a PPI, it is presumed that GERD has been effectively addressed. However, a remission of symptoms subsequent to PPI treatment does not always reflect healing of underlying pathology. The simplistic model of GERD, in which acid exposure equals degree of erosion, does not bear out in the literature. Animal models and in vitro research linking oxidative stress to esophageal damage continue to challenge the current model of pathogenesis. These underlying issues need more investigation and will ideally be considered in future research designed to prevent and treat GERD.

While older medications, like raft-forming agents based upon alginates, pectin's, and glycyrrhizin analogs have been proven to be effective and safe in mild-to-moderate disease, they have fallen out of favor, replaced by newer, more expensive agents.

Melatonin is a potentially attractive alternative therapy for GERD. It might directly address several underlying mechanisms (oxidative stress, infammation, motility, and gastrointestinal signaling). Its primary side effect is, not surprisingly, somnolence, which occurs in a majority of persons. While it has not been investigated, it is at least possible that the increased quality of sleep that occurs because of this side effect contributes in part to the therapeutic response to melatonin in GERD patients.

The use of compounds such as curcumin and quercetin has not been explored in human GERD trials, but the existing in vitro and animal data suggest these compounds warrant further investigation. The botanical combination Iberogast has shown efficacy in existing trials and has a low side effect profile. Further research on this botanical combination is warranted.

Evidence suggests acupuncture might play a therapeutic role in combination with PPIs for treatment of GERD. Its efficacy as a stand-alone treatment for this condition has not been investigated. More research on acupuncture in combination with other therapies and as a stand-alone approach should be conducted.

There is insufficient evidence to make any defnitive dietary recommendations for persons with GERD. Limited evidence suggests potential benefits from consuming a low-carbohydrate diet. Evidence also suggests that dietary changes that produce weight loss might benefit GERD.



References

1. Vakil, N, van Zanten SV, Kahrilas p, et al. Te Montreal definition and classification of gastro-esophageal reflux disease: a global evidence-based consensus. Am J Gastroenterol 2006;101:1900-1920.

2. Kahrilas PJ. Review article: gastro-oesophageal refhux disease as a functional gastrointestinal disorder. Aliment Pharmacol Ter 2004;20:50-55.

3. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut 2005;54:710-717.

4. Sharma P, Wani S, Romero Y, et al. Racial and geographic issues in gastroesophageal reflux disease. Am J Gastroenterol 2008;103:2669-2680.

5. Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol 2006;101:2128-2138.

6. Pohl H, Welch HG. The role of overdiagnosis and reclassifcation in the marked increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:142-146.

7. Sweet M P, Patti MG, Leard LE, et al. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Torac Cardiovasc Surg 2007;133:1078-1084.

8. Richter JE. Typical and atypical presentations of gastroesophageal reflux disease. The role of esophageal testing in diagnosis and management. Gastroenterol Clin North Am 1996;25:75-102.

9. Sontag SJ, O'Connell S, Khandelwal S, et al. Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 1990;99:613-620.

10. Molina-Infante J, Ferrando-Lamana L, Mateos-Rodriguez JM, et al. Overlap of reflux and eosinophilic esophagitis in two patients requiring different therapies: a review of the literature. World J Gastroenterol 2008;14:1463-1466.

11. Spergel JM. Eosinophilic esophagitis in adults and children: evidence for a food allergy component in many patients. Curr Opin Allergy Clin Immunol 2007;7:274-278.

12. Pandolfno JE, Shi G, Curry J, et al. Esophagogastric junction distensibility: a factor contributing to sphincter incompetence. Am J Physiol Gastrointest Liver Physiol 2002;282:G1052-G1058.

13. Festi D, Scaioli E, Baldi F, et al. Body weight, lifestyle, dietary habits, and gastroesophageal reflux disease. World J Gastroenterol 2009;15:1690-1701.

14. de Vries DR, van Herwaarden MA, Smout AJ, Samsom M. Gastroesophageal pressure gradients in gastroesophageal reflux disease: relations with hiatal hernia, body mass index, and esophageal acid exposure. Am J Gastroenterol 2008;103:1349-1354.

15. Wu JC, Mui LM, Cheung CM, et al. Obesity is associated with increased transient lower esophageal sphincter relaxation. Gastroenterology 2007;132:883-889.

16. Lee YC, Yen AM, Tai JJ, et al. The effect of metabolic risk factors on the natural course of gastro-oesophageal reflux disease. Gut 2009;58:174-178.

17. DeVault KR, Castell DO, American College of Gastorenterology. Updated guidelines for the diagnosis and treatment of gastroesophageal reflux disease. Am J Gastroenterol 2005;100:190-200.

18. Ronkainen J, Aro P, Storskrubb T, et al. Prevalence of Barrett's esophagus in the general population: an endoscopic study. Gastroenterology 2005;129:1825-1831.

19. Zagari RM, Fuccio L, Wallander MA, et al. Gastro-oesophageal reflux symptoms, oesophagitis and Barrett's oesophagus in the general population: the Loiano-Monghidoro study. Gut 2008;57:1354-1359.

20. Jones R, Junghard O, Dent J, et al. Development of the GerdQ, a tool for the diagnosis and management of gastro-oesophageal reflux disease in primary care. Aliment Pharmacol Ter 2009;30:1030-1038.

21. Boeckxstaens GE. Review article: the pathophysiology of gastro-oesophageal reflux disease. Aliment Pharmacol Ter 2007;26:149-160.

22. Bredenoord AJ, Weusten BL, Curvers WL, et al. Determinants of perception of heartburn and regurgitation. Gut 2006;55:313-318.

23. Tack J, Koek G, Demedts I, et al. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or both? Am J Gastroenterol 2004;99:981-988.

24. Kunsch S, Linhart T, Fensterer H, et al. Prevalence of a pathological DGER (duodeno-gastric-oesophageal reflux) in patients with clinical symptoms of reflux disease. Z Gastroenterol 2008;46:409-414. [Article in German]

25. Dvorak K, Payne CM, Chavarria M, et al. Bile acids in combination with low pH induce oxidative stress and oxidative DNA damage: relevance to the pathogenesis of Barrett's oesophagus. Gut 2007;56:763-771.

26. Dodds WJ, Dent J, Hogan WJ, et al. Mechanisms of gastroesophageal reflux in patients with reflux esophagitis. N Engl J Med 1982;307:1547-1552.

27. Stephen AM, Haddad AC, Philips SF. Passage of carbohydrate into the colon. Direct measurements in humans. Gastroenterology 1983;85:589-595.

28. Piche T, Zerbib F, Varannes SB, et al. Modulation by colonic fermentation of LES function in humans. Am J Physiol Gastrointest Liver Physiol 2000;278:G578-G584.

29. Schoeman MN, Tippett MD, Akkermans LM, et al. Mechanisms of gastroesophageal reflux in ambulant healthy human subjects. Gastroenterology 1995;108:83-91.

30. Ropert A, Cherbut C, Roze C, et al. Colonic fermentation and proximal gastric tone in humans. Gastroenterology 1996;111:289-296.

31. Eriksen CA, Cullen PT, Sutton D, et al. Abnormal esophageal transit in patients with typical reflux symptoms but normal endoscopic and pH profles. Am J Surg 1991;161:657-661.

32. Tack J. Recent developments in the pathophysiology and therapy of gastroesophageal reflux disease and nonerosive reflux disease. Curr Opin Gastroenterol 2005;21:454-460.

33. Emerenziani S, Sifrim D. Gastroesophageal reflux and gastric emptying, revisited. Curr Gastroenterol Rep 2005;7:190-195.

34. Penagini R, Hebbard G, Horowitz M. Motor function of the proximal stomach and visceral perception in gastro-oesophageal reflux disease. Gut 1998;42:251-257.

35. Miwa H, Kondo T, Oshima T, et al. Esophageal sensation and esophageal hypersensitivity - overview from bench to bedside. J Neurogastroenterol Motil 2010;16:353-362.

36. Sifrim D, Castell D, Dent J, Kahrilas PJ. Gastro-oesophageal reflux monitoring: review and consensus report on detection and defnitions of acid, non-acid, and gas refux. Gut 2004;53:1024-1031.

37. Smout AJ. Review article: the measurement of non-acid gastro-oesophageal reflux. Aliment Pharmacol Ter 2007;26:7-12.

38. Zerbib F, Roman S, Ropert A, et al. Esophageal pH-impedance monitoring and symptom analysis in GERD: a study in patients of and on therapy. Am J Gastroenterol 2006;101:1956-1963.

39. Mainie I, Tutuian R, Shay S, et al. Acid and non-acid reflux in patients with persistent symptoms despite acid suppressive therapy: a multicentre study using combined ambulatory impedance-pH monitoring. Gut 2006;55:1398-1402.

40. Sharma N, Agrawal A, Freeman J, et al. An analysis of persistent symptoms in acid-suppressed patients undergoing impedance-pH monitoring. Clin Gastroenterol Hepatol 2008;6:521-524.

41. Siddiqui A, Rodriguez-Stanley S, Zubaidi S, Miner PB Jr. Esophageal visceral sensitivity to bile salts in patients with functional heartburn and in healthy control subjects. Dig Dis Sci 2005;50:81-85.

42. El-Serag HB. Epidemiology of non-erosive reflux disease. Digestion 2008;78:6-10.

43. Dean BB, Gano AD Jr, Knight K, et al. Efectiveness of proton pump inhibitors in nonerosive reflux disease. Clin Gastroenterol Hepatol 2004;2:656-664.

44. Carlsson R, Frison L, Lundell L, et al. Relationship between symptoms, endoscopic findings and treatment outcome in reflux esophagitis. Gastroenterology 1996;110:A77.

45. El-Serag HB, Johanson JF. Risk factors for the severity of erosive esophagitis in Helicobacter pylori-negative patients with gastroesophageal reflux disease. Scand J Gastroenterol 2002;37:899-904.

46. Savarino E, Zentilin P, Tutuian R, et al. The role of nonacid reflux in NERD: lessons learned from impedance-pH monitoring in 150 patients of therapy. Am J Gastroenterol 2008;103:2685-2693.

47. Quigley EM. Gastro-oesophageal reflux disease - spectrum or continuum? QJM 1997;90:75-78.

48. Cameron AJ. Barrett's esophagus: prevalence and size of hiatal hernia. Am J Gastroenterol 1999;94:2054-2059.

49. Bardhan KD, Royston C, Nayyar AK. Reflux rising! An essay on witnessing a disease in evolution. Dig Liver Dis 2006;38:163-168.

50. Pace F, Bianchi Porro G. Gastroesophageal reflux disease: a typical spectrum disease (a new conceptual framework is not needed). Am J Gastroenterol 2004;99:946-949.

51. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures efective in patients with gastroesophageal reflux disease? An evidence-based approach. Arch Intern Med 2006;166:965-971.

52. Bulat R, Fachnie E, Chauhan U, et al. Lack of effect of spearmint on lower oesophageal sphincter function and acid reflux in healthy volunteers. Aliment Pharmacol Ter 1999;13:805-812.

53. No authors listed. An evidence-based appraisal of reflux disease management the Genval Workshop Report. Gut 1999;44:S1-S16.

54. Pettit M. Treatment of gastroesophageal reflux disease. Pharm World Sci 2005;27:432-435.

55. Khan M, Santana J, Donnellan C, et al. Medical treatments in the short term management of reflux oesophagitis. Cochrane Database Syst Rev 2007;(2):CD003244.

56. Vesper BJ, Altman KW, Elseth KM, et al. Gastroesophageal reflux disease (GERD): is there more to the story? ChemMedChem 2008;3:552-559.

57. Fass R, Sifrim D. Management of heartburn not responding to proton pump inhibitors. Gut 2009;58:295-309.

58. Johnsson F, Hatlebakk JG, Klintenberg AC, Roman J. Symptom-relieving effect of esomeprazole 40 mg daily in patients with heartburn. Scand J Gastroenterol 2003;38:347-353.

59. Fass R, Murthy U, Hayden CW, et al. Omeprazole 40 mg once a day is equally effective as lansoprazole 30 mg twice a day in symptom control of patients with gastro-oesophageal reflux disease (GERD) who are resistant to conventional-dose lansoprazole therapy - a prospective, randomized, multi-centre study. Aliment Pharmacol Ter 2000;14:1595-1603.

60. Pohle T, Domschke W. Results of short-and long-term medical treatment of gastroesophageal reflux disease (GERD). Langenbecks Arch Surg 2000;385:317-323.

61. Van Soest EM, Siersema PD, Dieleman JP, et al. Persistence and adherence to proton pump inhibitors in daily clinical practice. Aliment Pharmacol Ter 2006;24:377-385.

62. Pollock K, Grime J. The cost and cost-efectiveness of PPIs - GP perspectives and responses to a prescribing dilemma and their implications for the development of patient-centred healthcare. Eur J Gen Pract 2003;9:126-133,140.

63. Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217-1221.

64. Reimer C, Sondergaard B, Hilsted L, Bytzer P. Proton-pump inhibitor therapy induces acid-related symptoms in healthy volunteers after withdrawal of therapy. Gastroenterology 2009;137:80-87.

65. Gillen D, Wirz AA, Ardill JE, McColl KE. Rebound hypersecretion after omeprazole and its relation to on-treatment acid suppression and Helicobacter pylori status. Gastroenterology 1999;116:239-247.

66. Fossmark R, Johnsen G, Johanessen E, Waldum HL. Rebound acid hypersecretion after long-term inhibition of gastric secretion. Aliment Pharmacol Ter 2005;21:149-154.

67. Schenk BE, Kuipers EJ, Klinkenberg-Knol EC, et al. Hypergastrinaemia during long-term omeprazole therapy: influences of vagal nerve function, gastric emptying and Helicobacter pylori infection. Aliment Pharmacol Ter 1998;12:605-612.

68. Kuipers EJ, Lundell L, Klinkenberg-Knol EC, et al. Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication. N Engl J Med 1996; 334: 1018-1022.

69. Moayyedi P, Wason C, Peacock R, et al. Changing patterns of Helicobacter pylori gastritis in long-standing acid suppression. Helicobacter 2000;5:206-214.

70. Klinkenberg-Knol EC, Nelis F, Dent J, et al. Long-term omeprazole treatment in resistant gastroesophageal reflux disease: efficacy, safety, and infuence on gastric mucosa. Gastroenterology 2000;118:661-669.

71. Geboes K, Dekker W, Mulder CJ, et al. Long-term lansoprazole treatment for gastro-oesophageal reflux disease: clinical efficacy and infuence on gastric mucosa. Aliment Pharmacol Ter 2001;15:1819-1826.

72. Stolte M, Meining A, Schmitz JM, et al. Changes in Helicobacter pylori-induced gastritis in the antrum and corpus during 12 months of treatment with omeprazole and lansoprazole in patients with gastro-oesophageal reflux disease. Aliment Pharmacol Ter 1998;12:247-253.

73. Richter JE. H pylori: the bug is not all bad. Gut 2001;49:319-320.

74. Koike T, Ohara S, Sekine H, et al. Helicobacter pylori infection prevents erosive reflux oesophagitis by decreasing gastric acid secretion. Gut 2001;49:330-334.

75. Vicari JJ, Peek RM, Falk GW, et al. The seroprevalence of cagA-positive Helicobacter pylori strains in the spectrum of gastroesophageal reflux disease. Gastroenterology 1998;115:50-57.

76. Richter JE, Falk GW, Vaezi MF. Helicobacter pylori and gastroesophageal reflux disease: the bug may not be all bad. Am J Gastroenterol 1998;93:1800-1802.

77. Wu JC, Chan FK, Ching JY, et al. Effect of Helicobacter pylori eradication on treatment of gastro-oesophageal reflux disease: a double blind, placebo controlled, randomised trial. Gut 2004;53:174-179.

78. Dial S, Alrasadi K, Manoukian C, et al. Risk of Clostridium difcile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ 2004;171:33-38.

79. Choudhry MN, Soran H, Ziglam HM. Overuse and inappropriate prescribing of proton pump inhibitors in patients with Clostridium difficile-associated disease. QJM 2008;101:445-448.

80. Herzig SJ, Howell MD, Ngo LH, Marcantonio ER. Acid-suppressive medication use and the risk for hospital-acquired pneumonia. JAMA 2009;301:2120-2128.

81. Eurich DT, Sadowski CA, Simpson SH, et al. Recurrent community-acquired pneumonia in patients starting acid-suppressing drugs. Am J Med 2010;123:47-53.

82. Corley DA, Kubo A, Zhao W, Quesenberry C. Proton pump inhibitors and histamine-2 receptor antagonists are associated with hip fractures among at-risk patients. Gastroenterology 2010;139:93-101.

83. Ip S, Bonis P, Tatsioni A, et al. Comparative efectiveness of management strategies for gastroesophageal reflux disease. Comparative Efectiveness Reviews, No 1. Rockville, MD: Agency for Healthcare Research and Quality. December 2005. ncbi.nlm.nih.gov/ books/NBK42949/

84. Yancy WS Jr, Provenzale D, Westman EC. Improvement of gastroesophageal reflux disease after initiation of a low-carbohydrate diet: five brief case reports. Altern Ter Health Med 2001;7:120, 116-119.

85. Yudkin J, Evans E, Smith MG. The low-carbohydrate diet in the treatment of chronic dyspepsia. Proc Nutr Soc 1972;31:12A.

86. Austin GL, Tiny MT, Westman EC, et al. A very low-carbohydrate diet improves gastroesophageal reflux and its symptoms. Dig Dis Sci 2006;51:1307-1312.

87. Dickman R, Schif E, Holland A, et al. Clinical trial: acupuncture vs. doubling the proton pump inhibitor dose in refractory heartburn. Aliment Pharmacol Ter 2007;26:1333-1344.

88. Xu S, Zha H, Hou X, Chen J. Electroacupuncture accelerates solid gastric emptying in patients with functional dyspepsia. Gastroenterology 2004;126:T1163.

89. Chang X, Yan J, Yi S, et al. The afects of acupuncture at sibai and neiting acupoints on gastric peristalsis. J Tradit Chin Med 2001;21:286-288.

90. Kaada B. Successful treatment of esophageal dysmotility and Raynaud's phenomenon in systemic sclerosis and achalasia by transcutaneous nerve stimulation. Increase in plasma VIP concentration. Scand J Gastroenterol 1987;22:1137-1146.

91. Borjesson M, Pilhall M, Eliasson T, et al. Esophageal visceral pain sensitivity: effects of TENS and correlation with manometric findings. Dig Dis Sci 1998;43:1621-1628.

92. Bubenik GA, Hacker RR, Brown GM, Bartos L. Melatonin concentrations in the luminal fluid, mucosa and muscularis of the bovine and porcine gastrointestinal tract. J Pineal Res 1999;26:56-63.

93. Tan D, Manchester LC, Reiter RJ, et al. High physiological levels of melatonin in the bile of mammals. Life Sci 1999;65:2523-2529.

94. Tan DX, Manchester LC, Hardeland R, et al. Melatonin: a hormone, a tissue factor, an autocoid, a paracoid, and an antioxidant vitamin. J Pineal Res 2003;34:75-78.

95. Huether G, Poeggeller G, Reimer A, George A. Effect of tryptophan administration on circulating melatonin levels in chicks and rats: evidence for stimulation of melatonin synthesis and release in the gastrointestinal tract. Life Sci 1992;51:945-953.

96. Bubenik GA, Pang SF, Cockshut JR, et al. Circadian variation of portal, arterial and venous blood levels of melatonin in pigs and its relationship to food intake and sleep. J Pineal Res 2000;28:9-15.

97. Pandi-Perumal SR, Srinivasan V, Maestroni GJ, et al. Melatonin: nature's most versatile biological signal? FEBS J 2006;273:2813-2838.

98. Bubenik GA, Pang SF, Hacker RR, Smith PS. Melatonin concentrations in serum and tissues of porcine gastrointestinal tract and their relationship to the intake and passage of food. J Pineal Res 1996;21:251-256.

99. Konturek SJ, Zayachkivska O, Havryluk XO, et al. Protective influence of melatonin against acute esophageal lesions involves prostaglandins, nitric oxide, and sensory nerves. J Physiol Pharmacol 2007;58:361-377.

100. Konturek SJ, Konturek PC, Brzozowski T, Bubenik GA. Role of melatonin in upper gastrointestinal tract. J Physiol Pharmacol 2007;58:23-52.

101. Lahiri S, Singh P, Singh S, et al. Melatonin protects against experimental reflux esophagitis J Pineal Res 2009;46:207-213.

102. Pereira Rde S. Regression of gastro-esophageal reflux disease symptoms using dietary supplementation with melatonin, vitamins and amino acids: comparison with omeprazole. J Pineal Res 2006;41:195-200.

103. Kandil TS, Mousa AA, El-Gendy AA, Abbas AM. The potential therapeutic effect of melatonin in gastro-esophageal reflux disease. BMC Gastroenterol 2010;10:7.

104. Ku SK, Seo BI, Park JH, et al. Effect of Lonicerae flos extracts on reflux esophagitis with antioxidant activity. World J Gastroenterol 2009;15:4799-4805.

105. Inamori M, Akiyama T, Akimoto K, et al. Early effects of peppermint oil on gastric emptying: a crossover study using a continuous real-time 13C breath test (BreathID system). J Gastroenterol 2007;42:539-542.

106. Melzer J, Rosch W, Reichling J, et al. Meta-analysis: phytotherapy of functional dyspepsia with the herbal drug preparation STW 5 (Iberogast). Aliment Pharmacol Ter 2004;20:1279-1287.

107. Braden B, Caspary W, Borner N, et al. Clinical effects of STW 5 (Iberogast) are not based on acceleration of gastric emptying in patients with functional dyspepsia and gastroparesis. Neurogastroenterol Motil 2009;21:632-638.

108. Lambert JR, Korman MG, Nicholson L, Chan JG. In-vivo anti-refux and raft properties of alginates. Aliment Pharmacol Ter 1990;4:615-622.

109. Waterhouse ET, Washington C, Washington N. An investigation into the efficacy of the pectin based anti-reflux formulation-Aflurax. Int J Pharm 2000;209:79-85.

110. Amdrup E, Jakobsen BM. Reflux esophagitis treated with Gaviscon. Acta Chir Scand Suppl 1969;396:16-17.

111. Chatfeld S. A comparison of the efficacy of the alginate preparation, Gaviscon Advance, with placebo in the treatment of gastro-oesophageal reflux disease. Curr Med Res Opin 1999;15:152-159.

112. Farup PG, Heibert M, Hoeg V. Alternative vs. conventional treatment given on-demand for gastroesophageal reflux disease: a randomised controlled trial. BMC Complement Altern Med 2009;9:3.

113. Young GP, Nagy GS, Myren J, et al. Treatment of reflux oesophagitis with a carbenoxolone/antacid/alginate preparation. A double-blind controlled trial. Scand J Gastroenterol 1986;21:1098-1104.

114. Reed PI, Davies WA. Controlled trial of a new dosage form of carbenoxolone (Pyrogastrone) in the treatment of reflux esophagitis. Am J Dig Dis 1978;23:161-165.

115. Markham C, Reed PI. Pyrogastrone treatment of peptic oesophagitis: analysis of 104 patients treated during a 3 ?-year period. Scand J Gastroenterol Suppl 1980;65:73-82.

116. Maxton DG, Heald J, Whorwell PJ, Haboubi NY. Controlled trial of pyrogastrone and cimetidine in the treatment of reflux oesophagitis. Gut 1990;31:351-354.

117. Crowell PL, Elson CE, Bailey HH, et al. Human metabolism of the experimental cancer therapeutic agent d-limonene. Cancer Chemother Pharmacol 1994;35:31-37.

118. Wilkins JS Jr. Method for treating gastrointestinal disorders. U.S. Patent (6,420,435). July 16, 2002.

119. Lis-Balchin M, Ochocka RJ, Deans SG, et al. Bioactivity of the enantiomers of limonene. Med Sci Res 1996;24:309-310.

120. Lanas A, Royo Y, Ortego J, et al. Experimental esophagitis induced by acid and pepsin in rabbits mimicking human reflux esophagitis. Gastroenterology 1999;116:97-107.

121. Lanas AI, Blas JM, Ortego J, et al. Adaptation of esophageal mucosa to acid- and pepsin-induced damage: role of nitric oxide and epidermal growth factor. Dig Dis Sci 1997;42:1003-1012.

122. Orlando RC. Esophageal epithelial defenses against acid injury. Am J Gastroenterol 1994;89:S48-S52.

123. Rieder F, Biancani P, Harnett K, et al. Infammatory mediators in gastro-esophageal reflux disease: impact on esophageal motility, fibrosis, and carcinogenesis. Am J Physiol Gastrointest Liver Physiol 2010;298:G571-G581.

124. Si J, Behar J, Wands J, et al. STAT5 mediates PAF-induced NADPH oxidase NOX5-S expression in Barrett's esophageal adenocarcinoma cells. Am J Physiol Gastrointest Liver Physiol 2008;294:G174-G183.

125. Oh TY, Lee JS, Ahn BO, et al. Oxidative stress is more important than acid in the pathogenesis of reflux oesphagitis in rats. Gut 2001;49:364-371.

126. Rafee P, Nelson VM, Manley S, et al. Effect of curcumin on acidic pH-induced expression of IL-6 and IL-8 in human esophageal epithelial cells (HET-1A): role of PKC, MAPKs and NF-kappaB. Am J Physiol Gastrointest Liver Physiol 2009;296:G388-G398.

127. Rao CV, Vijayakumar M. Effect of quercetin, favonoids and alpha-tocopherol, an antioxidant vitamin, on experimental reflux oesophagitis in rats. Eur J Pharmacol 2008;589:233-238.

Размещено на allbest.ru

...