The use of Ghrelin and Ghrelin receptor agonists as a treatment for animal models of disease: Efficacy and mechanism

Current Pharmaceutical Design

Volumn 18, Issue 31, 2012, Pages 4779-4799

  Deboer, Mark D ^a  

^a UNIVERSITY OF VIRGINIA   (United States)

Author keywords

Animal models; Cachexia; Cancer; Chronic heart failure; Chronic kidney disease; Ghrelin; Treatment

Indexed keywords

BIM 28125; C REACTIVE PROTEIN; GHRELIN; GHRELIN RECEPTOR; GHRELIN RECEPTOR AGONIST; HEXARELIN; HORMONE RECEPTOR STIMULATING AGENT; IBUTAMOREN; INTERLEUKIN 6; MELANOCORTIN; MELANOCORTIN 4 RECEPTOR; NEUROPEPTIDE Y; PLACEBO; PROTEIN C FOS; SOMATOMEDIN C; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG;

AGING; ANOREXIA; ANTIINFLAMMATORY ACTIVITY; APPETITE; ARTHRITIS; ARTICLE; BLOOD PRESSURE REGULATION; BODY COMPOSITION; CACHEXIA; CANCER CHEMOTHERAPY; CANCER INHIBITION; CHRONIC KIDNEY DISEASE; CHRONIC KIDNEY FAILURE; CYTOKINE RELEASE; DISEASE ASSOCIATION; DISEASE MODEL; DOWN REGULATION; DRUG EFFICACY; DRUG HALF LIFE; ENERGY BALANCE; ENERGY EXPENDITURE; ENTERITIS; FATTY ACID ANALYSIS; FOOD INTAKE; HEART FAILURE; HEART MUSCLE ISCHEMIA; HEART OUTPUT; HUMAN; INFLAMMATION; LEAN BODY WEIGHT; LEFT ANTERIOR DESCENDING CORONARY ARTERY; NONHUMAN; OBESITY; OSMOTIC MINIPUMP; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN BLOOD LEVEL; PROTEIN DEGRADATION; PROTEIN EXPRESSION; REGULATORY MECHANISM; REPERFUSION INJURY; STOMACH PARESIS; SYMPATHETIC TONE; THERMAL INJURY; VASCULAR RESISTANCE; WEIGHT GAIN;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTINEOPLASTIC AGENTS; APPETITE REGULATION; APPETITE STIMULANTS; CACHEXIA; CARDIOTONIC AGENTS; DISEASE MODELS, ANIMAL; GHRELIN; HEART FAILURE; HUMANS; NEOPLASMS; RECEPTORS, GHRELIN; RENAL INSUFFICIENCY, CHRONIC;

EID: 84866434902     PISSN: 13816128     EISSN: 18734286     Source Type: Journal    
DOI: 10.2174/138161212803216951     Document Type: Article

References (230)

1. Tisdale MJ. Biology of cachexia. J. Natl Cancer Inst 1997; 89: 1763-1773.
2. Ahmad A, Duerksen DR, Munroe S, Bistrian BR. An evaluation of resting energy expenditure in hospitalized, severely underweight patients. Nutrition 1999; 15(5): 384-388.
3. Riley M, Elborn JS, McKane WR, Bell N, Stanford CF, Nicholls DP. Resting energy expenditure in chronic cardiac failure. Clin Sci (Lond) 1991; 80(6): 633-639.
4. Braun TP, Marks DL. Pathophysiology and treatment of inflammatory anorexia in chronic disease. J Cachexia Sarcopenia Muscle 2010; 1(2): 135-145.
5. DeBoer MD. What can anorexia nervosa teach us about appetite regulation? Nutrition 2011; 27(4): 405-406.
6. DeBoer MD. Melanocortin interventions in cachexia: how soon from bench to bedside? Curr Opin Clin Nutr Metab Care 2007; 10(4): 457-462.
7. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 1999; 402(6762): 656-660.
8. DeBoer MD. Ghrelin and cachexia: will treatment with GHSR-1a agonists make a difference for patients suffering from chronic wasting syndromes? Mol Cell Endocrinol 2011; 340(1): 97-105.
9. Nass RM, Gaylinn BD, Rogol AD, Thorner MO. Ghrelin and growth hormone: story in reverse. Proc Natl Acad Sci USA 2010; 107(19): 8501-8502.
10. Kirchner H, Gutierrez JA, Solenberg PJ, et al. GOAT links dietary lipids with the endocrine control of energy balance. Nat Med 2009; 15(7): 741-745.
11. Akamizu T, Takaya K, Irako T, et al. Pharmacokinetics, safety, and endocrine and appetite effects of ghrelin administration in young healthy subjects. Eur J Endocrinol 2004; 150(4): 447-455.
12. Hosoda H, Kojima M, Matsuo H, Kangawa K. Ghrelin and desacyl ghrelin: two major forms of rat ghrelin peptide in gastrointestinal tissue. Biochem Biophys Res Commun 2000; 279(3): 909-913.
13. Cummings DE, Weigle DS, Frayo RS, et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med 2002; 346(21): 1623-1630.
14. Asakawa A, Inui A, Kaga T, et al. Ghrelin is an appetitestimulatory signal from stomach with structural resemblance to motilin. Gastroenterology 2001; 120(2): 337-345.
15. Tschop M, Weyer C, Tataranni PA, Devanarayan V, Ravussin E, Heiman ML. Circulating ghrelin levels are decreased in human obesity. Diabetes 2001; 50(4): 707-709.
16. Madison LD, Scarlett JM, Levasseur P, et al. Prostacyclin signaling regulates circulating ghrelin during acute inflammation. J Endocrinol 2008; 196(2): 263-273.
17. Nakazato M, Murakami N, Date Y, et al. A role for ghrelin in the central regulation of feeding. Nature 2001; 409(6817): 194-198.
18. Guan XM, Yu H, Palyha OC, McKee KK, Feighner SD, Sirinathsinghji DJ, et al. Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Brain Res Mol Brain Res 1997; 48(1): 23-29.
19. Marks DL, Ling N, Cone RD. Role of the Central Melanocortin System in Cachexia. Cancer Res 2001; 61(4): 1432-1438.
20. DeBoer MD, Marks DL. Therapy insight: Use of melanocortin antagonists in the treatment of cachexia in chronic disease. Nat Clin Pract Endocrinol Metab 2006; 2(8): 459-466.
21. Scarlett JM, Jobst EE, Enriori PJ, et al. Regulation of Central Melanocortin Signaling by Interleukin-1{beta}. Endocrinology 2007; 148(9): 4217-4225.
22. Scarlett JM, Zhu X, Enriori PJ, et al. Regulation of agouti-related protein messenger ribonucleic acid transcription and peptide secretionby acute and chronic inflammation. Endocrinology 2008; 149(10): 4837-4845.
23. Cheung W, Yu PX, Little BM, Cone RD, Marks DL, Mak RH. Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest 2005; 115(6): 1659-1665.
24. Marks DL, Butler AA, Turner R, Brookhart GB, Cone RD. Differential role of melanocortin receptor subtypes in cachexia. Endocrinology 2003; 144(4): 1513-1523.
25. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Chronic central infusion of ghrelin increases hypothalamic neuropeptide Y and Agouti-related protein mRNA levels and body weight in rats. Diabetes 2001; 50(11): 2438-2443.
26. Kamegai J, Tamura H, Shimizu T, Ishii S, Sugihara H, Wakabayashi I. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 2000; 141(12): 4797-4800.
27. DeBoer MD, Marks DL. Cachexia: lessons from melanocortin antagonism. Trends Endocrinol Metab 2006; 17(5): 199-204.
28. Katz AM, Katz PB. Diseases of the heart in the works of Hippocrates. Br Heart J 1962; 24: 257-264.
29. Kofler S, Nickel T, Weis M. Role of cytokines in cardiovascular diseases: a focus on endothelial responses to inflammation. Clin Sci (Lond) 2005; 108(3): 205-213.
30. Spate U, Schulze PC. Proinflammatory cytokines and skeletal muscle. Curr Opin Clin Nutr Metab Care 2004; 7(3): 265-269.
31. Akiho H, Ihara E, Motomura Y, Nakamura K. Cytokine-induced alterations of gastrointestinal motility in gastrointestinal disorders. World J Gastrointest Pathophysiol 2011; 2(5): 72-81.
32. DeBoer MD, Scarlett JM, Levasseur PR, Grant WF, Marks DL. Administration of IL-1beta to the 4th ventricle causes anorexia that is blocked by agouti-related peptide and that coincides with activation of tyrosine-hydroxylase neurons in the nucleus of the solitary tract. Peptides 2009; 30(2): 210-218.
33. Ruud J, Blomqvist A. Identification of rat brainstem neuronal structures activated during cancer-induced anorexia. J Comp Neurol 2007; 504(3): 275-286.
34. Black B, Herr K, Fine P, et al. The relationships among pain, nonpain symptoms, and quality of life measures in older adults with cancer receiving hospice care. Pain Med 2011; 12(6): 880-889.
35. Vigano A, Donaldson N, Higginson IJ, Bruera E, Mahmud S, Suarez-Almazor M. Quality of life and survival prediction in terminal cancer patients: a multicenter study. Cancer 2004; 101(5): 1090-1098.
36. DeBoer MD. Emergence of ghrelin as a treatment for cachexia syndromes. Nutrition 2008; 24(9): 806-814.
37. Dewys WD, Begg C, Lavin PT, et al. Prognostic effect of weight loss prior to chemotherapy in cancer patients. Eastern Cooperative Oncology Group. Am J Med 1980; 69(4): 491-497.
38. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev 2009; 89(2): 381-410.
39. Tan BH, Fearon KC. Cachexia: prevalence and impact in medicine. Curr Opin Clin Nutr Metab Care 2008; 11(4): 400-407.
40. Bosaeus I, Daneryd P, Lundholm K. Dietary intake, resting energy expenditure, weight loss and survival in cancer patients. J Nutr 2002; 132(11 Suppl): 3465S-3466S.
41. Falconer JS, Fearon KC, Plester CE, Ross JA, Carter DC. Cytokines, the acute-phase response, and resting energy expenditure in cachectic patients with pancreatic cancer. Ann Surg 1994; 219(4): 325-331.
42. DeBoer MD. Animal models of anorexia and cachexia. Expert Opin Drug Discov 2009; 4(11): 1145-1155.
43. Hanada T, Toshinai K, Kajimura N, et al. Anti-cachectic effect of ghrelin in nude mice bearing human melanoma cells. Biochem Biophys Res Commun 2003; 301(2): 275-279.
44. Markison S, Foster AC, Chen C, et al. The regulation of feeding and metabolic rate and the prevention of murine cancer cachexia with a small-molecule melanocortin-4 receptor antagonist. Endocrinology 2005; 146(6): 2766-2773.
45. Nicholson JR, Kohler G, Schaerer F, Senn C, Weyermann P, Hofbauer KG. Peripheral administration of a melanocortin 4-receptor inverse agonist prevents loss of lean body mass in tumor-bearing mice. J Pharmacol Exp Ther 2006; 317(2): 771-777.
46. Jiang W, Tucci FC, Tran JA, et al. Pyrrolidinones as potent functional antagonists of the human melanocortin-4 receptor. Bioorg Med Chem Lett 2007; 17(20): 5610-5613.
47. Tran JA, Jiang W, Tucci FC, et al. Design, synthesis, in vitro, and in vivo characterization of phenylpiperazines and pyridinylpiperazines as potent and selective antagonists of the melanocortin-4 receptor. J Med Chem 2007; 50(25): 6356-6366.
48. Chen C, Tucci FC, Jiang W, et al. Pharmacological and pharmacokinetic characterization of 2-piperazine-alpha-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists. Bioorg Med Chem 2008; 16(10): 5606-5618.
49. Joppa MA, Gogas KR, Foster AC, Markison S. Central infusion of the melanocortin receptor antagonist agouti-related peptide (AgRP(83-132)) prevents cachexia-related symptoms induced by radiation and colon-26 tumors in mice. Peptides 2007; 28(3): 636-642.
50. Vos TJ, Caracoti A, Che JL, et al. Identification of 2-[2-[2-(5-bromo-2- methoxyphenyl)-ethyl]-3-fluorophenyl]-4,5-dihydro-1Himidazole (ML00253764), a small molecule melanocortin 4 receptor antagonist that effectively reduces tumor-induced weight loss in a mouse model. J Med Chem 2004; 47(7): 1602-1604.
51. Weyermann P, Dallmann R, Magyar J, et al. Orally available selective melanocortin-4 receptor antagonists stimulate food intake and reduce cancer-induced cachexia in mice. PLoS One 2009; 4(3): e4774.
52. DeBoer MD, Zhu XX, Levasseur P, et al. Ghrelin treatment causes increased food intake and retention of lean body mass in a rat model of cancer cachexia. Endocrinology 2007; 148(6): 3004-3012.
53. Ramos EJ, Middleton FA, Laviano A, et al. Effects of omega-3 fatty acid supplementation on tumor-bearing rats. J Am Coll Surg 2004; 199(5): 716-723.
54. Wang Z, Wang W, Qiu W, et al. Involvement of ghrelin-growth hormone secretagogue receptor system in pathoclinical profiles of digestive system cancer. Acta Biochim Biophys Sin (Shanghai) 2007; 39(12): 992-998.
55. Ramos EJ, Romanova IV, Suzuki S, et al. Effects of omega-3 fatty acids on orexigenic and anorexigenic modulators at the onset of anorexia. Brain Res 2005; 1046(1-2): 157-164.
56. Goncalves CG, Ramos EJ, Romanova IV, Suzuki S, Chen C, Meguid MM. Omega-3 fatty acids improve appetite in cancer anorexia, but tumor resecting restores it. Surgery 2006; 139(2): 202-208.
57. Mirza KA, Wyke SM, Tisdale MJ. Attenuation of muscle atrophy by an N-terminal peptide of the receptor for proteolysis-inducing factor (PIF). Br J Cancer 2011; 105(1): 83-88.
58. Todorov PT, Wyke SM, Tisdale MJ. Identification and characterization of a membrane receptor for proteolysis-inducing factor on skeletal muscle. Cancer Res 2007; 67(23): 11419-11427.
59. Rebeca R, Bracht L, Noleto GR, et al. Production of cachexia mediators by Walker 256 cells from ascitic tumors. Cell Biochem Funct 2008; 26(6): 731-738.
60. Cahlin C, Korner A, Axelsson H, Wang W, Lundholm K, Svanberg E. Experimental cancer cachexia: the role of host-derived cytokines interleukin (IL)-6, IL-12, interferon-gamma, and tumor necrosis factor alpha evaluated in gene knockout, tumor-bearing mice on C57 Bl background and eicosanoid-dependent cachexia. Cancer Res 2000; 60(19): 5488-5493.
61. Argiles JM, Busquets S, Garcia-Martinez C, Lopez-Soriano FJ. Mediators involved in the cancer anorexia-cachexia syndrome: past, present, and future. Nutrition 2005; 21(9): 977-985.
62. Kim S, Takahashi H, Lin WW, et al. Carcinoma-produced factors activate myeloid cells through TLR2 to stimulate metastasis. Nature 2009; 457(7225): 102-106.
63. Falconer JS, Fearon KC, Ross JA, et al. Acute-phase protein response and survival duration of patients with pancreatic cancer. Cancer 1995; 75(8): 2077-2082.
64. Deans C, Wigmore SJ. Systemic inflammation, cachexia and prognosis in patients with cancer. Curr Opin Clin Nutr Metab Care 2005; 8(3): 265-269.
65. Deans DA, Wigmore SJ, Gilmour H, Paterson-Brown S, Ross JA, Fearon KC. Elevated tumour interleukin-1beta is associated with systemic inflammation: A marker of reduced survival in gastrooesophageal cancer. Br J Cancer 2006; 95(11): 1568-1575.
66. Chen SZ, Qiu ZG. Combined treatment with GH, insulin, and indomethacin alleviates cancer cachexia in a mouse model. J Endocrinol 2011; 208(2): 131-136.
67. Grunberg SM, Deuson RR, Mavros P, et al. Incidence of chemotherapy-induced nausea and emesis after modern antiemetics. Cancer 2004; 100(10): 2261-2268.
68. Wang W, Andersson M, Iresjo BM, Lonnroth C, Lundholm K. Effects of ghrelin on anorexia in tumor-bearing mice with eicosanoid-related cachexia. Int J Oncol 2006; 28(6): 1393-1400.
69. Nikolopoulos D, Theocharis S, Kouraklis G. Ghrelin: a potential therapeutic target for cancer. Regul Pept 2010; 163(1-3): 7-17.
70. Raghay K, Garcia-Caballero T, Nogueiras R, et al. Ghrelin localization in rat and human thyroid and parathyroid glands and tumours. Histochem Cell Biol 2006; 125(3): 239-246.
71. Garcia JM, Garcia-Touza M, Hijazi RA, et al. Active ghrelin levels and active to total ghrelin ratio in cancer-induced cachexia. J Clin Endocrinol Metab 2005; 90(5): 2920-2926.
72. Shimizu Y, Nagaya N, Isobe T, et al. Increased plasma ghrelin level in lung cancer cachexia. Clin Cancer Res 2003; 9(2): 774-778.
73. Malendowicz W, Ziolkowska A, Szyszka M, Kwias Z. Elevated blood active ghrelin and unaltered total ghrelin and obestatin concentrations in prostate carcinoma. Urol Int 2009; 83(4): 471-475.
74. Neary NM, Small CJ, Wren AM, et al. Ghrelin increases energy intake in cancer patients with impaired appetite: acute, randomized, placebo-controlled trial. J Clin Endocrinol Metab 2004; 89(6): 2832-2836.
75. Pourtau L, Leemburg S, Roux P, et al. Hormonal, hypothalamic and striatal responses to reduced body weight gain are attenuated in anorectic rats bearing small tumors. Brain Behav Immun 2011; 25(4): 777-786.
76. Morley JE. Calories and cachexia. Curr Opin Clin Nutr Metab Care 2009; 12(6): 607-610.
77. Joppa MA, Gogas KR, Foster AC, Markison S. Central infusion of the melanocortin receptor antagonist agouti-related peptide (AgRP(83-132)) prevents cachexia-related symptoms induced by radiation and colon-26 tumors in mice. Peptides 2007; 28(3): 636-642.
78. Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8(12): 915-928.
79. Aje TO, Miller M. Cardiovascular disease: A global problem extending into the developing world. World J Cardiol 2009; 1(1): 3-10.
80. von Haehling S, Lainscak M, Springer J, Anker SD. Cardiac cachexia: a systematic overview. Pharmacol Ther 2009; 121(3): 227-252.
81. Anker SD, Ponikowski P, Varney S, et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet 1997; 349(9058): 1050-1053.
82. Anker SD, Swan JW, Volterrani M, et al. The influence of muscle mass, strength, fatigability and blood flow on exercise capacity in cachectic and non-cachectic patients with chronic heart failure. Eur Heart J 1997; 18(2): 259-269.
83. Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol 2002; 85(1): 51-66.
84. Filippatos GS, Anker SD, Kremastinos DT. Pathophysiology of peripheral muscle wasting in cardiac cachexia. Curr Opin Clin Nutr Metab Care 2005; 8(3): 249-254.
85. Rauchhaus M, Coats AJ, Anker SD. The endotoxin-lipoprotein hypothesis. Lancet 2000; 356(9233): 930-933.
86. Levine B, Kalman J, Mayer L, Fillit HM, Packer M. Elevated circulating levels of tumor necrosis factor in severe chronic heart failure. N Engl J Med 1990; 323(4): 236-241.
87. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol 1996; 27(5): 1201-1206.
88. Torre-Amione G, Kapadia S, Lee J, et al. Tumor necrosis factoralpha and tumor necrosis factor receptors in the failing human heart. Circulation 1996; 93(4): 704-711.
89. Li Y, Takemura G, Okada H, et al. Reduction of inflammatory cytokine expression and oxidative damage by erythropoietin in chronic heart failure. Cardiovasc Res 2006; 71(4): 684-694.
90. Thakker GD, Frangogiannis NG, Bujak M, et al. Effects of dietinduced obesity on inflammation and remodeling after myocardial infarction. Am J Physiol Heart Circ Physiol 2006; 291(5): H2504-H2514.
91. Anker SD, Egerer KR, Volk HD, Kox WJ, Poole-Wilson PA, Coats AJ. Elevated soluble CD14 receptors and altered cytokines in chronic heart failure. Am J Cardiol 1997; 79(10): 1426-1430.
92. Ono K, Matsumori A, Shioi T, Furukawa Y, Sasayama S. Cytokine gene expression after myocardial infarction in rat hearts: possible implication in left ventricular remodeling. Circulation 1998; 98(2): 149-156.
93. Yndestad A, Damas JK, Oie E, Ueland T, Gullestad L, Aukrust P. Systemic inflammation in heart failure--the whys and wherefores. Heart Fail Rev 2006; 11(1): 83-92.
94. Aker S, Belosjorow S, Konietzka I, et al. Serum but not myocardial TNF-alpha concentration is increased in pacing-induced heart failure in rabbits. Am J Physiol Regul Integr Comp Physiol 2003; 285(2): R463-R469.
95. DeBoer MD. Update on melanocortin interventions for cachexia: progress toward clinical application. Nutrition 2010; 26(2): 146-151.
96. Scarlett JM, Bowe DD, Zhu X, Batra AK, Grant WF, Marks DL. Genetic and pharmacologic blockade of central melanocortin signaling attenuates cardiac cachexia in rodent models of heart failure. J Endocrinol 2010; 206(1): 121-130.
97. Basra AK, Scarlett JM, Bowe DD, Steiner RA, Marks DL. Central melanocortin blockade attenuates cardiac cachexia in a rat model of chronic heart failure. J Investig Med 2008 2008; 56: 229-230.
98. Bowe DD, Scarlett JM, Basra AK, Steiner RA, Marks DL. Blockade of central melanocortin signaling promotes accumulation of lean body mass in rodent models of chronic heart failure. J Investig Med 2007; 55: S77.
99. Akashi YJ, Palus S, Datta R, et al. No effects of human ghrelin on cardiac function despite profound effects on body composition in a rat model of heart failure. Int J Cardiol 2009; 137(3): 267-275.
100. Nagaya N, Uematsu M, Kojima M, et al. Chronic administration of ghrelin improves left ventricular dysfunction and attenuates development of cardiac cachexia in rats with heart failure. Circulation 2001; 104(12): 1430-1435.
101. Palus S, Akashi Y, von Haehling S, Anker SD, Springer J. The influence of age and sex on disease development in a novel animal model of cardiac cachexia. Int J Cardiol 2009; 133(3): 388-393.
102. King MK, Gay DM, Pan LC, et al. Treatment with a growth hormone secretagogue in a model of developing heart failure: effects on ventricular and myocyte function. Circulation 2001; 103(2): 308-313.
103. Schwenke DO, Tokudome T, Kishimoto I, et al. Early ghrelin treatment after myocardial infarction prevents an increase in cardiac sympathetic tone and reduces mortality. Endocrinology 2008; 149(10): 5172-5176.
104. Shimizu Y, Nagaya N, Teranishi Y, et al. Ghrelin improves endothelial dysfunction through growth hormone-independent mechanisms in rats. Biochem Biophys Res Commun 2003; 310(3): 830-835.
105. Nagaya N, Miyatake K, Uematsu M, et al. Hemodynamic, renal, and hormonal effects of ghrelin infusion in patients with chronic heart failure. J Clin Endocrinol Metab 2001; 86(12): 5854-5859.
106. Lund LH, Williams JJ, Freda P, LaManca JJ, LeJemtel TH, Mancini DM. Ghrelin resistance occurs in severe heart failure and resolves after heart transplantation. Eur J Heart Fail 2009; 11(8): 789-794.
107. Akashi YJ, Palus S, Datta R, et al. No effects of human ghrelin on cardiac function despite profound effects on body composition in a rat model of heart failure. Int J Cardiol 2009; 137(3): 267-275.
108. Xu XB, Pang JJ, Cao JM, et al. GH-releasing peptides improve cardiac dysfunction and cachexia and suppress stress-related hormones and cardiomyocyte apoptosis in rats with heart failure. Am J Physiol Heart Circ Physiol 2005; 289(4): H1643-H1651.
109. Tivesten A, Bollano E, Caidahl K, et al. The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction. Endocrinology 2000; 141(1): 60-66.
110. Anker SD, von Haehling S. The obesity paradox in heart failure: accepting reality and making rational decisions. Clin Pharmacol Ther 2011; 90(1): 188-190.
111. Bodart V, Bouchard JF, McNicoll N, et al. Identification and characterization of a new growth hormone-releasing peptide receptor in the heart. Circ Res 1999; 85(9): 796-802.
112. Muccioli G, Ghe C, Ghigo MC, et al. Specific receptors for synthetic GH secretagogues in the human brain and pituitary gland. J Endocrinol 1998; 157(1): 99-106.
113. Beiras-Fernandez A, Kreth S, Weis F, et al. Altered myocardial expression of ghrelin and its receptor (GHSR-1a) in patients with severe heart failure. Peptides 2010; 31(12): 2222-2228.
114. Shih H, Lee B, Lee RJ, Boyle AJ. The aging heart and postinfarction left ventricular remodeling. J Am Coll Cardiol 2011; 57(1): 9-17.
115. Baldanzi G, Filigheddu N, Cutrupi S, et al. Ghrelin and des-acyl ghrelin inhibit cell death in cardiomyocytes and endothelial cells through ERK1/2 and PI 3-kinase/AKT. J Cell Biol 2002; 159(6): 1029-1037.
116. Filigheddu N, Gnocchi VF, Coscia M, et al. Ghrelin and des-acyl ghrelin promote differentiation and fusion of C2C12 skeletal muscle cells. Mol Biol Cell 2007; 18(3): 986-994.
117. Lear PV, Iglesias MJ, Feijoo-Bandin S, et al. Des-acyl ghrelin has specific binding sites and different metabolic effects from ghrelin in cardiomyocytes. Endocrinology 2010; 151(7): 3286-3298.
118. Filigheddu N, Fubini A, Baldanzi G, et al. Hexarelin protects H9c2 cardiomyocytes from doxorubicin-induced cell death. Endocrine 2001; 14(1): 113-119.
119. De Gennaro Colonna V, Rossoni G, Bernareggi M, Muller EE, Berti F. Hexarelin, a growth hormone-releasing peptide, discloses protectant activity against cardiovascular damage in rats with isolated growth hormone deficiency. Cardiologia 1997; 42(11): 1165-1172.
120. Rossoni G, De Gennaro Colonna V, Bernareggi M, Polvani GL, Muller EE, Berti F. Protectant activity of hexarelin or growth hormone against postischemic ventricular dysfunction in hearts from aged rats. J Cardiovasc Pharmacol 1998; 32(2): 260-265.
121. Weekers F, Van Herck E, Isgaard J, Van den Berghe G. Pretreatment with growth hormone-releasing peptide-2 directly protects against the diastolic dysfunction of myocardial stunning in an isolated, blood-perfused rabbit heart model. Endocrinology 2000; 141(11): 3993-3999.
122. Locatelli V, Rossoni G, Schweiger F, et al. Growth hormoneindependent cardioprotective effects of hexarelin in the rat. Endocrinology 1999; 140(9): 4024-4031.
123. Nagaya N, Moriya J, Yasumura Y, et al. Effects of ghrelin administration on left ventricular function, exercise capacity, and muscle wasting in patients with chronic heart failure. Circulation 2004; 110(24): 3674-3679.
124. Bisi G, Podio V, Valetto MR, et al. Cardiac effects of hexarelin in hypopituitary adults. Eur J Pharmacol 1999; 381(1): 31-38.
125. Bisi G, Podio V, Valetto MR, et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest 1999; 22(4): 266-272.
126. Isgaard J, Granata R. Ghrelin in cardiovascular disease and atherogenesis. Mol Cell Endocrinol 2011; 340(1): 59-64.
127. Soeki T, Kishimoto I, Schwenke DO, et al. Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction. Am J Physiol Heart Circ Physiol 2008; 294(1): H426-H432.
128. Wu R, Zhou M, Das P, et al. Ghrelin inhibits sympathetic nervous activity in sepsis. Am J Physiol Endocrinol Metab 2007; 293(6): E1697-E1702.
129. Matsumura K, Tsuchihashi T, Fujii K, Abe I, Iida M. Central ghrelin modulates sympathetic activity in conscious rabbits. Hypertension 2002; 40(5): 694-699.
130. Lin Y, Matsumura K, Fukuhara M, Kagiyama S, Fujii K, Iida M. Ghrelin acts at the nucleus of the solitary tract to decrease arterial pressure in rats. Hypertension 2004; 43(5): 977-982.
131. Huda MS, Mani H, Dovey T, et al. Ghrelin inhibits autonomic function in healthy controls, but has no effect on obese and vagotomized subjects. Clin Endocrinol (Oxf) 2010; 73(5): 678-685.
132. Nguyen CT, Aaronson A, Morrissey RP, Agarwal M, Willix RD, Schwarz ER. Myths and truths of growth hormone and testosterone therapy in heart failure. Expert Rev Cardiovasc Ther 2011; 9(6): 711-720.
133. Qureshi AR, Alvestrand A, Danielsson A, et al. Factors predicting malnutrition in hemodialysis patients: a cross-sectional study. Kidney Int 1998; 53(3): 773-782.
134. NIDDK. Kidney and Urologic Diseases Statistics for the United States. http://kidney.niddk.nih.gov/kudiseases/pubs/kustats/; Website accessed 11/1/11.
135. DeBoer MD, Zhu X, Levasseur PR, et al. Ghrelin treatment of chronic kidney disease: improvements in lean body mass and cytokine profile. Endocrinology 2008; 149(2): 827-835.
136. Mitch WE. Malnutrition: a frequent misdiagnosis for hemodialysis patients. J Clin Invest 2002; 110(4): 437-439.
137. Pickering WP, Price SR, Bircher G, Marinovic AC, Mitch WE, Walls J. Nutrition in CAPD: serum bicarbonate and the ubiquitinproteasome system in muscle. Kidney Int 2002; 61(4): 1286-1292.
138. Cheung WW, Kuo HJ, Markison S, et al. Peripheral administration of the melanocortin-4 receptor antagonist NBI-12i ameliorates uremia-associated cachexia in mice. J Am Soc Nephrol 2007; 18(9): 2517-2524.
139. Cheung WW, Rosengren S, Boyle DL, Mak RH. Modulation of melanocortin signaling ameliorates uremic cachexia. Kidney Int 2008; 74(2): 180-186.
140. Bergstrom J. Why are dialysis patients malnourished? Am J Kidney Dis 1995; 26(1): 229-241.
141. Mitch WE., Robert H Herman Memorial Award in Clinical Nutrition Lecture, 1997. Mechanisms causing loss of lean body mass in kidney disease. Am J Clin Nutr 1998; 67(3): 359-366.
142. Heimburger O, Lonnqvist F, Danielsson A, Nordenstrom J, Stenvinkel P. Serum immunoreactive leptin concentration and its relation to the body fat content in chronic renal failure. J Am Soc Nephrol 1997; 8(9): 1423-1430.
143. Mak RH, Cheung W, Cone RD, Marks DL. Orexigenic and anorexigenic mechanisms in the control of nutrition in chronic kidney disease. Pediatr Nephrol 2005; 20(3): 427-431.
144. Kaysen GA, Rathore V, Shearer GC, Depner TA. Mechanisms of hypoalbuminemia in hemodialysis patients. Kidney Int 1995; 48(2): 510-516.
145. Avesani CM, Draibe SA, Kamimura MA, Colugnati FA, Cuppari L. Resting energy expenditure of chronic kidney disease patients: influence of renal function and subclinical inflammation. Am J Kidney Dis 2004; 44(6): 1008-1016.
146. Utaka S, Avesani CM, Draibe SA, Kamimura MA, Andreoni S, Cuppari L. Inflammation is associated with increased energy expenditure in patients with chronic kidney disease. Am J Clin Nutr 2005; 82(4): 801-805.
147. Mitch WE, Goldberg AL. Mechanisms of muscle wasting. The role of the ubiquitin-proteasome pathway. N Engl J Med 1996; 335(25): 1897-905.
148. Goodman MN. Tumor necrosis factor induces skeletal muscle protein breakdown in rats. Am J Physiol 1991; 260(5 Pt 1): E727-E730.
149. Naufel MF, Bordon M, de Aquino TM, Ribeiro EB, de Abreu Carvalhaes JT. Plasma levels of acylated and total ghrelin in pediatric patients with chronic kidney disease. Pediatr Nephrol 2010; 25(12): 2477-2482.
150. Yoshimoto A, Mori K, Sugawara A, et al. Plasma ghrelin and desacyl ghrelin concentrations in renal failure. J Am Soc Nephrol 2002; 13(11): 2748-2752.
151. Arbeiter AK, Buscher R, Petersenn S, Hauffa BP, Mann K, Hoyer PF. Ghrelin and other appetite-regulating hormones in paediatric patients with chronic renal failure during dialysis and following kidney transplantation. Nephrol Dial Transplant 2009; 24(2): 643-646.
152. Iglesias P, Diez JJ, Fernandez-Reyes MJ, Codoceo R, Alvarez-Fidalgo P, Bajo MA, et al. Serum ghrelin concentrations in patients with chronic renal failure undergoing dialysis. Clin Endocrinol (Oxf) 2006; 64(1): 68-73.
153. Jarkovska Z, Hodkova M, Sazamova M, et al. Plasma levels of active and total ghrelin in renal failure: a relationship with GH/IGF-I axis. Growth Horm IGF Res 2005; 15(6): 369-376.
154. Rodriguez Ayala E, Pecoits-Filho R, Heimburger O, Lindholm B, Nordfors L, Stenvinkel P. Associations between plasma ghrelin levels and body composition in end-stage renal disease: a longitudinal study. Nephrol Dial Transplant 2004; 19(2): 421-426.
155. Perez-Fontan M, Cordido F, Rodriguez-Carmona A, et al. Acute plasma ghrelin and leptin responses to oral feeding or intraperitoneal hypertonic glucose-based dialysate in patients with chronic renal failure. Kidney Int 2005; 68(6): 2877-2885.
156. Mak RH, Cheung WW. Is ghrelin a biomarker for mortality in endstage renal disease? Kidney Int 2011; 79(7): 697-699.
157. Mafra D, Guebre-Egziabher F, Cleaud C, et al. Obestatin and ghrelin interplay in hemodialysis patients. Nutrition 2010; 26(11/12):1100-1104.
158. Zhang JV, Ren PG, Avsian-Kretchmer O, et al. Obestatin, a peptide encoded by the ghrelin gene, opposes ghrelin's effects on food intake. Science 2005; 310(5750): 996-999.
159. Mitch WE. Insights into the abnormalities of chronic renal disease attributed to malnutrition. J Am Soc Nephrol 2002; 13(Suppl 1): S22-S27.
160. Ashby DR, Ford HE, Wynne KJ, et al. Sustained appetite improvement in malnourished dialysis patients by daily ghrelin treatment. Kidney Int 2009; 76(2): 199-206.
161. Tschop M, Smiley DL, Heiman ML. Ghrelin induces adiposity in rodents. Nature 2000; 407(6806): 908-913.
162. Perez-Tilve D, Heppner K, Kirchner H, et al. Ghrelin-induced adiposity is independent of orexigenic effects. Faseb J 2011; 25(8): 2814-2822.
163. Takeda R, Nishimatsu H, Suzuki E, et al. Ghrelin improves renal function in mice with ischemic acute renal failure. J Am Soc Nephrol 2006; 17(1): 113-121.
164. Laurent V, Jaubert-Miazza L, Desjardins R, Day R, Lindberg I. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 2004; 145(2): 519-528.
165. Dixit VD, Schaffer EM, Pyle RS, et al. Ghrelin inhibits leptin- and activation-induced proinflammatory cytokine expression by human monocytes and T cells. J Clin Invest 2004; 114(1): 57-66.
166. Granado M, Priego T, Martin AI, Villanua MA, Lopez-Calderon A. Ghrelin receptor agonist GHRP-2 prevents arthritis-induced increase in E3 ubiquitin-ligating enzymes MuRF1 and MAFbx gene expression in skeletal muscle. Am J Physiol Endocrinol Metab 2005; 289(6): E1007-W1014.
167. Granado M, Priego T, Martin AI, Villanua MA, Lopez-Calderon A. Anti-inflammatory effect of the ghrelin agonist growth hormonereleasing peptide-2 (GHRP-2) in arthritic rats. Am J Physiol Endocrinol Metab 2005; 288(3): E486-E492.
168. Johannsson G, Bengtsson BA, Ahlmen J. Double-blind, placebocontrolled study of growth hormone treatment in elderly patients undergoing chronic hemodialysis: anabolic effect and functional improvement. Am J Kidney Dis 1999; 33(4): 709-717.
169. Hansen TB, Gram J, Jensen PB, et al. Influence of growth hormone on whole body and regional soft tissue composition in adult patients on hemodialysis. A double-blind, randomized, placebocontrolled study. Clin Nephrol 2000; 53(2): 99-107.
170. Bailey JL, Zheng B, Hu Z, Price SR, Mitch WE. Chronic kidney disease causes defects in signaling through the insulin receptor substrate/phosphatidylinositol 3-kinase/Akt pathway: implications for muscle atrophy. J Am Soc Nephrol 2006; 17(5): 1388-1394.
171. Conjard A, Ferrier B, Martin M, Caillette A, Carrier H, Baverel G. Effects of chronic renal failure on enzymes of energy metabolism in individual human muscle fibers. J Am Soc Nephrol 1995; 6(1): 68-74.
172. Siew ED, Pupim LB, Majchrzak KM, Shintani A, Flakoll PJ, Ikizler TA. Insulin resistance is associated with skeletal muscle protein breakdown in non-diabetic chronic hemodialysis patients. Kidney Int 2007; 71(2): 146-152.
173. Shinohara K, Shoji T, Emoto M, et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 2002; 13(7): 1894-1900.
174. Barazzoni R, Zhu X, Deboer M, et al. Combined effects of ghrelin and higher food intake enhance skeletal muscle mitochondrial oxidative capacity and AKT phosphorylation in rats with chronic kidney disease. Kidney Int 2010; 77(1): 23-28.
175. Venables G, Hunne B, Bron R, Cho HJ, Brock JA, Furness JB. Ghrelin receptors are expressed by distal tubules of the mouse kidney. Cell Tissue Res 2011; 346(1): 135-139.
176. Kemp BA, Howell NL, Gray JT, Keller SR, Nass RM, Padia SH. Intrarenal ghrelin infusion stimulates distal nephron-dependent sodium reabsorption in normal rats. Hypertension 2011; 57(3): 633-639.
177. Rajan D, Wu R, Shah KG, Jacob ACGF., Wang P. Human ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve. Surgery 2011; e-pub ahead of print.
178. van Ginhoven TM, Huisman TM, van den Berg JW, Ijzermans JN, Delhanty PJ, de Bruin RW. Preoperative fasting induced protection against renal ischemia/reperfusion injury is independent of ghrelin in mice. Nutr Res 2010; 30(12): 865-869.
179. Baker PD, Morzorati SL, Ellett ML. The pathophysiology of chemotherapy- induced nausea and vomiting. Gastroenterol Nurs 2005; 28(6): 469-480.
180. Hiura Y, Takiguchi S, Yamamoto K, et al. Fall in plasma ghrelin concentrations after cisplatin-based chemotherapy in esophageal cancer patients. Int J Clin Oncol 2011; e-pub ahead of print.
181. Yakabi K, Sadakane C, Noguchi M, et al. Reduced ghrelin secretion in the hypothalamus of rats due to cisplatin-induced anorexia. Endocrinology 2010; 151(8): 3773-3782.
182. Liu YL, Malik NM, Sanger GJ, Andrews PL. Ghrelin alleviates cancer chemotherapy-associated dyspepsia in rodents. Cancer Chemother Pharmacol 2006; 58(3): 326-333.
183. Garcia JM, Cata JP, Dougherty PM, Smith RG. Ghrelin prevents cisplatin-induced mechanical hyperalgesia and cachexia. Endocrinology 2008; 149(2): 455-460.
184. Fahim MA, Kataya H, El-Kharrag R, Amer DA, Al-Ramadi B, Karam SM. Ghrelin attenuates gastrointestinal epithelial damage induced by doxorubicin. World J Gastroenterol 2011; 17(33): 3836-3841.
185. Perboni S, Bowers C, Kojima S, Asakawa A, Inui A. Growth hormone releasing peptide 2 reverses anorexia associated with chemotherapy with 5-fluoruracil in colon cancer cell-bearing mice. World J Gastroenterol 2008; 14(41): 6303-6305.
186. Strasser F, Lutz TA, Maeder MT, et al. Safety, tolerability and pharmacokinetics of intravenous ghrelin for cancer-related anorexia/cachexia: a randomised, placebo-controlled, double-blind, double-crossover study. Br J Cancer 2008; 98(2): 300-308.
187. Wo JM, Ejskjaer N, Hellstrom PM, et al. Randomised clinical trial: ghrelin agonist TZP-101 relieves gastroparesis associated with severe nausea and vomiting--randomised clinical study subset data. Aliment Pharmacol Ther 2011; 33(6): 679-688.
188. Fraser GL, Venkova K, Hoveyda HR, Thomas H, Greenwood-Van Meerveld B. Effect of the ghrelin receptor agonist TZP-101 on colonic transit in a rat model of postoperative ileus. Eur J Pharmacol 2009; 604(1-3): 132-137.
189. Camilleri M, Papathanasopoulos A, Odunsi ST. Actions and therapeutic pathways of ghrelin for gastrointestinal disorders. Nat Rev Gastroenterol Hepatol 2009; 6(6): 343-352.
190. Ejskjaer N, Dimcevski G, Wo J, et al. Safety and efficacy of ghrelin agonist TZP-101 in relieving symptoms in patients with diabetic gastroparesis: a randomized, placebo-controlled study. Neurogastroenterol Motil 2010; 22(10): 1069-e1281.
191. Fielding RA, Vellas B, Evans WJ, et al. Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia. J Am Med Dir Assoc 2011; 12(4): 249-256.
192. Thomas DR. Use of orexigenic medications in geriatric patients. Am J Geriatr Pharmacother 2011; 9(2): 97-108.
193. Toshinai K, Mondal MS, Shimbara T, et al. Ghrelin stimulates growth hormone secretion and food intake in aged rats. Mech Ageing Dev 2007; 128(2): 182-186.
194. Yukawa M, Weigle DS, Davis CD, Marck BT, Wolden-Hanson T. Peripheral ghrelin treatment stabilizes body weights of senescent male Brown Norway rats at baseline and after surgery. Am J Physiol Regul Integr Comp Physiol 2008; 294(5): R1453-R1460.
195. Nass R, Pezzoli SS, Oliveri MC, et al. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med 2008; 149(9): 601-611.
196. Nass R, Johannsson G, Christiansen JS, Kopchick JJ, Thorner MO. The aging population--is there a role for endocrine interventions? Growth Horm IGF Res 2009; 19(2): 89-100.
197. Kowal-Vern A, Sharp-Pucci MM, Walenga JM, Dries DJ, Gamelli RL. Trauma and thermal injury: comparison of hemostatic and cytokine changes in the acute phase of injury. J Trauma 1998; 44(2): 325-329.
198. Bessey PQ, Jiang ZM, Johnson DJ, Smith RJ, Wilmore DW. Posttraumatic skeletal muscle proteolysis: the role of the hormonal environment. World J Surg 1989; 13(4): 465-470; discussion 71.
199. Balasubramaniam A, Wood S, Joshi R, et al. Ghrelin stimulates food intake and growth hormone release in rats with thermal injury: synthesis of ghrelin. Peptides 2006; 27(7): 1624-4631.
200. Jeschke MG, Barrow RE, Mlcak RP, Herndon DN. Endogenous anabolic hormones and hypermetabolism: effect of trauma and gender differences. Ann Surg 2005; 241(5): 759-767; discussion 67-8.
201. Sallam HS, Oliveira HM, Gan HT, Herndon DN, Chen JD. Ghrelin improves burn-induced delayed gastrointestinal transit in rats. Am J Physiol Regul Integr Comp Physiol 2007; 292(1): R253-R257.
202. Balasubramaniam A, Joshi R, Su C, et al. Ghrelin inhibits skeletal muscle protein breakdown in rats with thermal injury through normalizing elevated expression of E3 ubiquitin ligases MuRF1 and MAFbx. Am J Physiol Regul Integr Comp Physiol 2009; 296(4): R893-R901.
203. Sehirli O, Sener E, Sener G, Cetinel S, Erzik C, Yegen BC. Ghrelin improves burn-induced multiple organ injury by depressing neutrophil infiltration and the release of pro-inflammatory cytokines. Peptides 2008; 29(7): 1231-1240.
204. Karagiozoglou-Lampoudi T, Trachana M, Agakidis C, et al. Ghrelin levels in patients with juvenile idiopathic arthritis: relation to anti-tumor necrosis factor treatment and disease activity. Metabolism 2011; 60(10): 1359-1362.
205. Koca SS, Ozgen M, Aydin S, Dag S, Evren B, Isik A. Ghrelin and obestatin levels in rheumatoid arthritis. Inflammation 2008; 31(5): 329-335.
206. Otero M, Nogueiras R, Lago F, Dieguez C, Gomez-Reino JJ, Gualillo O. Chronic inflammation modulates ghrelin levels in humans and rats. Rheumatology (Oxford) 2004; 43(3): 306-310.
207. Gonzalez-Gay MA, Garcia-Unzueta MT, Berja A, et al. Antitumour necrosis factor alpha therapy modulates ghrelin in patients with severe rheumatoid arthritis. Ann Rheum Dis 2008; 67(11): 1644-166.
208. Jeffery P, McDonald V, Tippett E, McGuckin M. Ghrelin in gastrointestinal disease. Mol Cell Endocrinol 2011; 340(1): 35-43.
209. Poitras P, Polvino WJ, Rocheleau B. Gastrokinetic effect of ghrelin analog RC-1139 in the rat. Effect on post-operative and on morphine induced ileus. Peptides 2005; 26(9): 1598-1601.
210. Qiu WC, Wang ZG, Wang WG, Yan J, Zheng Q. Gastric motor effects of ghrelin and growth hormone releasing peptide 6 in diabetic mice with gastroparesis. World J Gastroenterol 2008; 14(9): 1419-1424.
211. Qiu WC, Wang ZG, Wang WG, Yan J, Zheng Q. Therapeutic effects of ghrelin and growth hormone releasing peptide 6 on gastroparesis in streptozotocin-induced diabetic guinea pigs in vivo and in vitro. Chin Med J (Engl) 2008; 121(13): 1183-1188.
212. Murray CD, Martin NM, Patterson M, et al. Ghrelin enhances gastric emptying in diabetic gastroparesis: a double blind, placebo controlled, crossover study. Gut 2005; 54(12): 1693-1698.
213. Tack J, Depoortere I, Bisschops R, Verbeke K, Janssens J, Peeters T. Influence of ghrelin on gastric emptying and meal-related symptoms in idiopathic gastroparesis. Aliment Pharmacol Ther 2005; 22(9): 847-853.
214. Binn M, Albert C, Gougeon A, et al. Ghrelin gastrokinetic action in patients with neurogenic gastroparesis. Peptides 2006; 27(7): 1603-1606.
215. Ejskjaer N, Vestergaard ET, Hellstrom PM, et al. Ghrelin receptor agonist (TZP-101) accelerates gastric emptying in adults with diabetes and symptomatic gastroparesis. Aliment Pharmacol Ther 2009; 29(11): 1179-1187.
216. Wargin W, Thomas H, Clohs L, et al. Contribution of protein binding to the pharmacokinetics of the ghrelin receptor agonist TZP-101 in healthy volunteers and adults with symptomatic gastroparesis: two randomized, double-blind studies and a binding profile study. Clin Drug Investig 2009; 29(6): 409-418.
217. Abraham C, Cho JH. Inflammatory bowel disease. N Engl J Med 2009; 361(21): 2066-2078.
218. Thayu M, Shults J, Burnham JM, Zemel BS, Baldassano RN, Leonard MB. Gender differences in body composition deficits at diagnosis in children and adolescents with Crohn's disease. Inflamm Bowel Dis 2007; 13(9): 1121-1128.
219. DeBoer MD, Li Y. Puberty is delayed in male mice with dextran sodium sulfate colitis out of proportion to changes in food intake, body weight, and serum levels of leptin. Pediatr Res 2011; 69(1): 34-39.
220. DeBoer MD, Li Y, Cohn S. Colitis causes delay in puberty in female mice out of proportion to changes in leptin and corticosterone. J Gastroenterol 2010; 45(3): 277-284.
221. DeBoer MD, Barnes BH. The importance of treatment regimens and pubertal status for growth in IBD. J Pediatr 2009; 154(6): 936-937; author reply 7.
222. Ballinger AB, Savage MO, Sanderson IR. Delayed puberty associated with inflammatory bowel disease. Pediatr Res 2003; 53(2): 205-210.
223. DeBoer MD. Use of ghrelin as a treatment for inflammatory bowel disease: mechanistic considerations. Int J Pept 2011; 2011: 189-242.
224. Gonzalez-Rey E, Chorny A, Delgado M. Therapeutic action of ghrelin in a mouse model of colitis. Gastroenterology 2006; 130(6): 1707-1720.
225. Konturek PC, Brzozowski T, Engel M, et al. Ghrelin ameliorates colonic inflammation. Role of nitric oxide and sensory nerves. J Physiol Pharmacol 2009; 60(2): 41-47.
226. De Smet B, Thijs T, Moechars D, et al. Endogenous and exogenous ghrelin enhance the colonic and gastric manifestations of dextran sodium sulphate-induced colitis in mice. Neurogastroenterol Motil 2009; 21(1): 59-70.
227. Kojouharoff G, Hans W, Obermeier F, et al. Neutralization of tumour necrosis factor (TNF) but not of IL-1 reduces inflammation in chronic dextran sulphate sodium-induced colitis in mice. Clin Exp Immunol 1997; 107(2): 353-358.
228. Wirtz S, Neufert C, Weigmann B, Neurath MF. Chemically induced mouse models of intestinal inflammation. Nat Protoc 2007; 2(3): 541-546.
229. Yamamoto T, Nakahigashi M, Umegae S, Matsumoto K. Enteral nutrition for the maintenance of remission in Crohn's disease: a systematic review. Eur J Gastroenterol Hepatol 2010; 22(1): 1-8.
230. Zachos M, Tondeur M, Griffiths AM. Enteral nutritional therapy for induction of remission in Crohn's disease. Cochrane Database Syst Rev 2007(1): CD000542.