News Column

Patent Issued for Use of a Ghrelin Agonist to Improve the Catabolic Effects of Glucocorticoid Treatment

June 16, 2014



By a News Reporter-Staff News Editor at Clinical Trials Week -- According to news reporting originating from Alexandria, Virginia, by NewsRx journalists, a patent by the inventors Tulipano, Giovanni (Cusago, IT); Giustina, Andrea (Brescia, IT); Dong, Zheng Xin (Holliston, MA); Culler, Michael DeWitt (Hopkinton, MA), filed on November 2, 2011, was published online on June 3, 2014 (see also Ipsen Pharma S.A.S.).

The assignee for this patent, patent number 8741835, is Ipsen Pharma S.A.S. (Boulogne, FR).

Reporters obtained the following quote from the background information supplied by the inventors: "Glucocorticoids are a class of steroid hormones characterized by an ability to bind with the cortisol receptor and trigger similar effects. Glucocorticoids have potent anti-inflammatory and immunosuppressive properties and as such are the best-known class of anti-inflammatory active ingredients. Owing to their broad range of uses and their great anti-inflammatory action, corticoid preparations are therapeutic agents of first choice in a wide variety of inflammatory diseases, such as, for example, diseases of the rheumatoid group, allergies, inflammatory diseases of the lungs, heart, and intestines, bronchial asthma, hyperproliferative diseases of the skin (psoriasis), eczemas, auto-immune diseases, or states of shock.

"Dexamethasone, a synthetic member of the glucocorticoid class of hormones which exhibits anti-inflammatory and immunosuppressive properties which are 40 times more potent than naturally-occurring hydrocortisone and having the following structure,

"##STR00001## 9-fluoro-11.beta.,17,21-trihydroxy-16a-methylpregna-1,4-diene-3,20-dione, has been shown to augment the antiemetic effect of 5-HT.sub.3 receptor antagonists. Dexamethasone is used to treat many inflammatory and autoimmune conditions, such as rheumatoid arthritis. It is also given to cancer patients undergoing chemotherapy to counteract certain side-effects.

"Glucocorticoids, particularly dexamethasone, have been used for years to treat preterm infants who have or are at risk for chronic lung disease (The, T. F. et al., Early Postnatal Dexamethasone Therapy for the Prevention of Chronic Lung Disease in Preterm Infants with Respiratory Distress Syndrome: A Multicenter Clinical Trial, 1997, 100:715-6). These agents often have the short-term benefits of improving lung compliance and facilitating early weaning from mechanical ventilation. Newborns, with extremely low birth weight (ELBW), traditionally receive early postnatal dexamethasone therapy to treat and/or prevent severe respiratory distress syndrome and the subsequent onset of chronic lung disease.

"Glucocorticoids, however, suppress growth hormone secretion. Human growth hormone (also may be referred to herein as 'GH') is a single-chain-polypeptide consisting of 191 amino acids (molecular weight 21,500). Disulfide bonds link positions 53 and 165 and positions 182 and 189 (Niall, Nature, New Biology, (1971), 230: 90). Effects of growth hormone on the tissues of the body can generally be described as anabolic (building up). Like most other protein hormones, GH acts by interacting with a specific receptor on the surface of cells. Height growth in childhood is the best known effect of GH action. GH also stimulates production of insulin-like growth factor 1 (may also be referred to herein as 'IGF-1') which demonstrates growth-stimulating effects on a wide variety of tissues. GH also serves many other metabolic functions such as increasing calcium retention and mineralization in bones, increasing muscle mass by inducing protein synthesis, stimulating the immune system, reducing liver uptake of glucose thus contributing to the maintenance and function of pancreatic islets and promoting lipolysis, which results in some reduction of adipose tissue (body fat) and rising amounts of free fatty acids and glycerol in the blood.

"The pulsatile release of growth hormone from the pituitary somatotrops is regulated by two hypothalamic neuropeptides: growth hormone-releasing hormone and somatostatin. Growth hormone-releasing hormone stimulates release of growth hormone whereas somatostatin inhibits secretion of growth hormone (Frohman et al., Endocrinology Review (1986) 7:223-53 and Strobi et al., Pharmacology Review (1994) 46:1-34). Most GH deficiencies are caused by defects in GH release, not primary defects in pituitary synthesis of the hormone itself. Increasing GH secretion can be achieved by stimulating or inhibiting various neurotransmitter systems in the brain and hypothalamus. As a result, the development of synthetic growth hormone-releasing agents to stimulate pituitary GH secretion is being pursued and may have several advantages over expensive and inconvenient GH replacement therapy. By acting along physiologic regulatory pathways, the most desirable agents would stimulate pulsatile GH secretion, and excessive levels of GH that have been associated with the undesirable side effects of exogenous GH administration would be avoided by virtue of intact negative feedback loops.

"It is hypothesized that the pathogenesis of glucocorticoid mediated growth inhibition is most likely multifactorial in nature involving, partial growth hormone resistance, suppression of IGF-1 activity, and antagonism of insulin activity. These factors all influence carbohydrate and lipid metabolism.

"By inhibiting GH secretion, elevated glucocorticoid levels can induce protein catabolism which in turn can lead to the degradation of skeletal muscle or the atrophy of intestinal villi. Deficiency in growth hormone results in a variety of medical disorders. The consequences of acquired GH deficiency include profound reduction in lean body mass and concomitant increase in total body fat, particularly in the truncal region. Decreased skeletal and cardiac muscle mass and muscle strength lead to a significant reduction in exercise capacity. Bone density is also reduced.

"Concern has been expressed regarding the effects of early dexamethasone therapy on somatic growth because glucocorticoids have been shown to alter cell size and DNA synthesis in animal models (Cotterrell M. et al., Effects of Corticosteroids on the Biochemical Maturation of Rat Brain: Postnatal Cell Formation, J. Neurochem., 1972, 19:2151-67). In addition, it has been found that dexamethasone therapy may compromise the accretion of bone mineral and this affect the velocity of bone growth, even when energy intake increases (Weiler, H. A. et al., Longitudinal Assessment of Growth and Bone Mineral Accretion in Prematurely Born Infants Treated for Chronic Lung Disease with Dexamethasone, Early Hum. Dev., 1997, 47:271-86 and Gibson, A. T. et al., Growth Retardation After Dexamethasone Administration: Assessment by Knemometry, Arch. Dis. Child, 1993, 69:505-9).

"As reported in the New England Journal of Medicine, children who received early postnatal dexamethasone therapy for severe respiratory distress of prematurity were observed to have more neuromotor and cognitive function impairment and disability at school age than premature children not treated with dexamethasone. A study conducted at the China Medical University, Taichung, Taiwan, revealed that children treated with dexamethasone had significantly smaller head circumference and significantly lower mean height. In addition, dexamethasone-treated children were observed to evidence significantly poorer motor skills and motor coordination as well as poorer visual-motor integration as compared to children not treated with dexamethasone. The observed increase in neurodevelopmental dysfunction in neonates treated with dexamethasone led the Taiwanese researchers to recommend the discontinuation of use of a dexamethasone regimen to chronic lung disease in children despite its benefits due to its adverse effects on somatic growth at school age (Hendry, J., Postnatal Dexamethasone Treatment Associate with Later Neuromotor and Cognitive Function Impairment and Disability, 2004, N. England J. Med., 350:1304-13).

"Glucocorticoid therapy is considered essential to the management of asthma; such treatments are often given on a daily basis and for an extended period of time. Recent studies have shown that glucocorticoid administration, while alleviating some symptoms of asthma, may also lead to airway damage or airway remodeling (see Dorscheid, D. R. et al., 'Apoptosis of airway epithelial cells induced by corticosteroids', Am. J. Respir. Crit. Care Med., 2001, 164:1939-1947). As noted by Dorscheid, treatment of asthma with corticosteroids such as dexamethasone and the resulting induction of cell death 'raises the possibility that at least one of the major components of chronic airway damage in asthma, epithelial shedding and denudation, may in part result from a major therapy for the disease.'

"Patients who must take large doses of pharmacological glucocorticoids, such as dexamethasone, can develop Cushing's syndrome if exposed to high enough doses over an extended period of time. Cushing's syndrome is a condition which is associated with a number of negative catabolic effects, including reduced growth velocity and lean body mass. A person suffering from Cushing's syndrome usually has a large, round face (commonly referred to as a 'moon face') with slender arms and legs in proportion to the thickened trunk. The catabolic effects of this disease results in limited muscle capacity which leads to pronounced physical weakness. The skin becomes thin, bruises easily and heals poorly when bruised or cut. The heightened glucocorticoid levels associated with Cushing's syndrome, over time, results in chronic, elevated blood pressure, osteoporosis, diminished resistance to infections, the development of kidney stones and diabetes. Mental disturbances, including depression and hallucinations, have been found to occur in persons having Cushing's syndrome. Women usually experience irregular menstrual cycles. Children with Cushing's syndrome grow slowly and remain short. In some people, the adrenal glands also produce large amounts of androgens. Chronic glucocorticoid excess associated with Cushing's syndrome, left untreated, increases the risk of premature death.

"Ghrelin likely enhances the activity of growth hormone releasing hormone (GHRH)-secreting neurons while concomitantly acting as a functional somatostatin (SS) antagonist (Ghigo, E. et al., Eur J Endocrinol (1997) 136(5):445-60). The observed ability of ghrelin to enhance food intake, increase food assimilation and gastric emptying, together with its ability to increase GH levels, thus promoting prompt nutrient incorporation into muscle and fat reserves, indicates that ghrelin may have therapeutic potential to treat indications wherein protein catabolism is a symptom.

"Long-term administration of glucocorticoids is one of the most used treatments in clinical medicine but is known to suppress GH secretion and action. In fact, glucocorticoids inhibit pulsatile GH release, reduce GH receptor expression and signal transduction and inhibit IGF-1 bioactivity. Recognition of glucocorticoid-mediated antagonism of GH secretion and action has renewed interest in GH therapy or treatments to stimulate GH release as a potential means to reverse some of the most harmful side effects of glucocorticoid long-term treatment, such as growth inhibition and catabolic effects. Different studies suggest that the detrimental effects of glucocorticoid can be variably overcome by GH treatment, but long-term GH therapy also has the potential for adverse effects and requires further surveillance and study. It has been extensively demonstrated in humans and animals that the inhibitory effects of long-term glucocorticoid administration on GH secretion are mediated by increased somatostatin tone. Synthetic GHS appear to stimulate GH release, in part, through inhibition of somatostatin pathway; indeed, GHRP-6 is able to completely counteract glucocorticoid-mediated GH-inhibition in the rat.

"It is a primary objective in the art to maximize the beneficial effects of glucocorticoids, in particular dexamethasone, while minimizing their adverse effects. The catabolic side effects of glucocorticoids prevent this class of substances from being put to an even broader range of therapeutic uses. Despite the reduced side-effect potential of modern corticoids, especially long-term treatment with active ingredients of this class of substances remains critical. Thus, there exists in the art the need for agents and methods to counteract the negative effects of and, thus to enhance the beneficial effects of, the long term administration of glucocorticoids."

In addition to obtaining background information on this patent, NewsRx editors also obtained the inventors' summary information for this patent: "This invention relates to a method and pharmaceutical composition for inhibiting the effect of glucocorticoids on growth hormone secretion, and more particularly to the pharmaceutical administration comprising a ghrelin analog, for example, [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2), which has been found useful as a ghrelin agonist to counteract the catabolic effects of dexamethasone and other natural glucocorticoids.

"Ghrelin is a naturally-occurring peptide having the following sequence: H-Gly-Ser-Ser-Phe-Leu-Ser-Pro-Glu-His-Gln-Arg-Val-Gln-Gln-Arg-Lys-Glu-Ser- -Lys-Lys-Pro-Pro-Ala-Lys-Leu-Gln-Pro-Arg-NH.sub.2 (Kojima M. et al. Nature (1999) 402(6762):656-60; SEQ ID NO:1). Ghrelin is produced by epithelial cells lining the fundus of the stomach which stimulate appetite and adiposity. Ghrelin levels are increased prior to a meal and decreased thereafter. Ghrelin levels in the plasma of obese individuals are lower than those in leaner individuals and levels of ghrelin increases during the time of the day from midnight to dawn in thinner individuals suggesting a flaw in the circulatory systems of obese individuals (Yildiz, B. et al., Proc. Natl. Acad. Sci. USA (2004) 101:10434-9) thus leading to the belief that ghrelin has the ability to regulate homeostasis.

"Ghrelin was discovered to powerfully stimulate growth hormone secretion from the anterior pituitary gland and is believed to be an endogenous ligand for the GH secretagogues (GHS) subtype-1a receptor (hereinafter may be referred to as 'GHS-1a'; Kojima et al., Nature (1999) 402:656-60) both in animals and in humans (Ukkola, O et al., 2002 Ann. Med. (2002) 34:102-8).

"In a first embodiment, the invention provides a method to ameliorate the catabolic effects of excess glucocorticoids in an individual in need of such treatment comprising administering to the individual a therapeutically effective amount of a ghrelin agonist. In one aspect of said first embodiment, the ghrelin agonist is [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2). In another aspect, the ghrelin agonist useful for any of the methods described herein is selected from the group consisting of:

"TABLE-US-00001 (SEQ ID NO: 3) (Dap.sup.3(octanesulfonyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 4) (Aib.sup.2, A6c.sup.5)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 5) (Aib.sup.2,6)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 6) (Aib.sup.2, 3-Pal.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 7) (A5c.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 8) (Act.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 9) (Aib.sup.2, Act.sup.6)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 10) (Aib.sup.2, Abu.sup.6)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 11) (Aib.sup.2, 4-Hyp.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 12) (Aib.sup.2, Thz.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 13) (Aib.sup.2, Pip.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 14) (Aib2, Dhp.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 15) (Aib.sup.2,8)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 16) (Aib.sup.2, 4-Pal.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 17) (Aib.sup.2, Taz.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 18) (Aib.sup.2,10)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 19) (Aib.sup.2, Tic.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 20) (A6c.sup.5)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 21) (3-Pal.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 22) (Aib.sup.8)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 23) (2-Thi.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 24) (Aib.sup.2, Cha.sup.5)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 25) (Aib.sup.2, Glu.sup.3(NH-hexyl), 4-Hyp.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 26) ((Aib.sup.2,8, Glu.sup.3(NH-hexyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 27) (Aib.sup.2, Glu.sup.3(NH-hexyl), 3-Pal.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 28) (Aib.sup.2, Glu.sup.3(NH-hexyl), 4-Pal.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 29) (Aib.sup.2, Glu.sup.3(NH-hexyl), Taz.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 30) (Aib.sup.2, Glu.sup.3(NH-hexyl), 2-Thi.sup.9)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 31) (Aib.sup.2,10, Glu.sup.3(NH-hexyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 32) (Glu.sup.3(NH-hexyl), 4-Hyp.sup.7)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 33) (Glu.sup.3(NH-hexyl), Aib.sup.8)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 34) (Aib.sup.2,12, Glu.sup.3(NH-hexyl), 4-Pal.sup.9, Orn.sup.15)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 35) (Glu.sup.3(O-hexyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 36) (Aib.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 37) (Glu.sup.3(NH-hexyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 38) (Ac-Gly.sup.1, Aib.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 39) (n-butyryl-Gly.sup.1)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 40) (isobutyryl-Gly.sup.1)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 41) (n-octanoyl-Gly.sup.1)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 42) Cys.sup.3(S(CH.sub.2).sub.9CH.sub.3)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 43) (Lys.sup.5)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 44) Inp-D-2-Nal-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 45) H-Inp-D-1-Nal-D-Trp-3-Pal-Lys-NH.sub.2; (SEQ ID NO: 46) H-Inp-D-2-Nal-D-Trp-Orn-Lys-NH.sub.2; (SEQ ID NO: 47) H-Inp-D-Bip-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 48) H-Inp-D-2-Nal-D-Trp-Pff-Lys-NH.sub.2; (SEQ ID NO: 49) H-Inp-D-2-Nal-D-Trp-2-Thi-Lys-NH.sub.2; (SEQ ID NO: 50) H-Inp-D-2-Nal-D-Trp-Taz-Lys-NH.sub.2; (SEQ ID NO: 51) H-Inp-D-Dip-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 52) H-Inp-D-Bpa-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 53) H-Inp-D-2-Nal-D-Bpa-Phe-Lys-NH.sub.2; (SEQ ID NO: 54) H-Inp-D-2-Nal-D-Trp-3-Pal-NH.sub.2; (SEQ ID NO: 55) H-Inp-D-2-Nal-D-Trp-4-Pal-NH.sub.2; (SEQ ID NO: 56) H-Inp-D-1-Nal-D-Trp-3-Pal-NH.sub.2; (SEQ ID NO: 57) H-Inp-D-Bip-D-Trp-Phe-NH.sub.2; (SEQ ID NO: 58) H-Inp-D-2-Nal-D-Trp-Thr(Bzl)-NH.sub.2; (SEQ ID NO: 59) H-Inp-D-2-Nal-D-Trp-Pff-NH.sub.2; (SEQ ID NO: 60) H-Inp-D-2-Nal-D-Trp-2-Thi-NH.sub.2; (SEQ ID NO: 61) H-Inp-D-2-Nal-D-Trp-Taz-NH.sub.2; (SEQ ID NO: 62) H-Inp-D-Dip-D-Trp-Phe-NH.sub.2; (SEQ ID NO: 63) H-Inp-D-2-Nal-D-Dip-Phe-NH.sub.2; (SEQ ID NO: 64) H-Inp-D-Bal-D-Trp-Phe-NH.sub.2; (SEQ ID NO: 65) H-Inp-D-2-Nal-D-Bal-Phe-NH.sub.2; (SEQ ID NO: 66) H-Inp-D-2-Nal-D-Trp-3-Pal-Lys-NH.sub.2; (SEQ ID NO: 67) H-Inp-D-Trp-D-2-Nal(T)-Pim; (SEQ ID NO: 68) H-Inp-D-Bal-D-Trp-2-Thi-Lys-NH.sub.2; (SEQ ID NO: 69) H-Inp-D-Bal-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 7) H-Inp-D-1-Nal-D-Trp-2-Thi-Lys-NH.sub.2; (SEQ ID NO: 71) H-Inp-D-2-Nal-D-Trp-Phe-Apc-NH.sub.2; (SEQ ID NO: 72) H-Inp-D-1-Nal-D-Trp-Phe-Apc-NH.sub.2; (SEQ ID NO: 73) H-Inp-D-Bal-D-Trp-Phe-Apc-NH.sub.2; (SEQ ID NO: 74) H-Apc-D-2-Nal-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 75) H-Apc-D-1-Nal-D-Trp-2-Thi-Lys-NH.sub.2; (SEQ ID NO: 76) H-Inp-D-1-Nal-D-Trp-2-Thi-NH.sub.2; (SEQ ID NO: 77) H-Apc-D-1-Nal-D-Trp-Phe-NH.sub.2; (SEQ ID NO: 78) H-Inp-D-2-Nal-D-Trp(.PSI.)-Pim; (SEQ ID NO: 79) H-Inp-D-1-Nal-D-Trp(.PSI.)-Pim; (SEQ ID NO: 80) H-Inp-D-Bal-D-Trp(.PSI.)-Pim; (SEQ ID NO: 81) H-Aib-D-Ser(Bzl)-D-Trp(.PSI.)-Pim; (SEQ ID NO: 82) H-Inp-D-1-Nal-D-Trp-Taz-Lys-NH.sub.2; (SEQ ID NO: 83) H-Inp-D-Bal-D-Trp-Taz-Lys-NH.sub.2; (SEQ ID NO: 84) H-Apc-D-1-Nal-D-Trp-Taz-Lys-NH.sub.2; (SEQ ID NO: 85) H-Apc-D-Bal-D-Trp-Taz-Lys-NH.sub.2;

"(SEQ ID NO: 86) H-Apc-D-Bal-D-Trp-2-Thi-Lys-NH.sub.2; (SEQ ID NO: 87) H-Apc-D-Bal-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 88) H-Apc-D-1-Nal-D-Trp-Phe-Apc-NH.sub.2; (SEQ ID NO: 89) H-Apc-D-Bal-D-Trp-Phe-Apc-NH.sub.2; (SEQ ID NO: 90) H-Apc-D-1-Nal-D-1-Nal-Phe-Apc-NH.sub.2; (SEQ ID NO: 91) H-Apc-D-1-Nal-D-2-Nal-Phe-Apc-NH.sub.2; (SEQ ID NO: 92) H-Apc-D-1-Nal-D-1-Nal-Phe-Lys-NH.sub.2; (SEQ ID NO: 93) H-Apc-D-Bal-D-1-Nal-Phe-Apc-NH.sub.2; (SEQ ID NO: 94) H-Apc-D-Bal-D-2-Nal-Phe-Apc-NH.sub.2; (SEQ ID NO: 95) H-Apc-D-Bal-D-2-Nal-Phe-Lys-NH.sub.2; (SEQ ID NO: 96) H-Apc-D-1-Nal-D-Trp-2-Thi-NH.sub.2; (SEQ ID NO: 97) H-Apc-D-Bal-D-Trp-Phe-NH.sub.2; (SEQ ID NO: 98) H-Apc-D-1-Nal-D-Trp-Taz-NH.sub.2; (SEQ ID NO: 99) H-Apc-D-Bal-D-Trp-2-Thi-NH.sub.2; (SEQ ID NO: 100) H-Apc-D-Bal-D-Trp-Taz-NH.sub.2; (SEQ ID NO: 101) H-Apc-D-2-Nal-D-Trp-2-Thi-NH.sub.2; (SEQ ID NO: 102) H-Apc-D-2-Nal-D-Trp-Taz-NH.sub.2; (SEQ ID NO: 103) H-Inp-D-1-Nal-D-Trp-Taz-Apc-NH.sub.2; (SEQ ID NO: 104) H-Inp-D-Bal-D-Trp-Taz-Apc-NH.sub.2; (SEQ ID NO: 105) H-Apc-D-1-Nal-D-Trp-Taz-Apc-NH.sub.2; (SEQ ID NO: 106) H-Apc-D-Bal-D-Trp-Taz-Apc-NH.sub.2; (SEQ ID NO: 107) H-Inp-D-2-Nal-D-Trp-4-Pal-Lys-NH.sub.2; (SEQ ID NO: 108) H-Inp-D-2-Nal-D-Trp-Thr(Bzl)-Lys-NH.sub.2; (SEQ ID NO: 109) H-Apc-D-Bal-D-1-Nal-Phe-Lys-NH.sub.2; (SEQ ID NO: 110) H-Inp-D-1-Nal-D-Trp-2-Thi-Apc-NH.sub.2; (SEQ ID NO: 111) H-Inp-D-Bal-D-Trp-2-Thi-Apc-NH.sub.2; (SEQ ID NO: 112) H-Apc-D-1-Nal-D-Trp-2-Thi-Apc-NH.sub.2; (SEQ ID NO: 113) H-Apc-D-Bal-D-Trp-2-Thi-Apc-NH.sub.2; (SEQ ID NO: 114) H-Apc-D-1-Nal-D-Trp-Phe-Lys-NH.sub.2; (SEQ ID NO: 115) (Aib.sup.2,8, Glu(NH-hexyl).sup.3,17)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 116) (Inp.sup.1, Aib.sup.2,10, Glu(NH-hexyl).sup.3)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 117) (1-Apc.sup.1, Aib.sup.2,10, Glu(NH-hexyl).sup.3)-hGhrelin(1-28)NH.sub.2; (SEQ ID NO: 118) (Inp.sup.1)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 119) (Inp.sup.1, Aib.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 120) (Inp.sup.1, Aib.sup.2, Glu(NH-hexyl).sup.3)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 121) (Inp.sup.1, Aib.sup.2,10)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 122) (Inp.sup.1, Aib.sup.2,8)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 123) (Inp.sup.1, Aib.sup.2, Ser(n-octanoyl).sup.17)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 124) (Inp.sup.1, Ser(n-octanoyl).sup.17)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 125) (Asp.sup.3(NH-heptyl))hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 126) (des-Ser.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 127) (des-Gly.sup.1, des-Ser.sup.2)hGhrelin(1-28)-NH.sub.2; (SEQ ID NO: 128) (Aib.sup.1)hGhrelin(1-28)-NH.sub.2;; and (SEQ ID NO: 129) (Asp.sup.3(O-hexyl))hGhrelin(1-28)-NH.sub.2.

"In another aspect of said first embodiment, the excess glucocorticoids are the result of a disease or a condition. In another aspect of said first embodiment, the excess glucocorticoids are the result of the long term administration of glucocorticoids to the individual. In a further aspect of the immediately foregoing, the administered glucocorticoid is dexamethasone. In another aspect of said first embodiment, the glucocorticoid induced catabolic effects include, but are not limited to, a reduction in growth, a reduction in growth rate, a reduction in body weight, a reduction in lean body mass, a reduction in IGF-1 levels and/or a reduction in bone mass. The individual receiving the method of the invention to ameliorate a reduction in growth, a reduction in growth rate, a reduction in body weight, a reduction in lean body mass, a reduction in IGF-levels and/or a reduction in bone mass is a child or an adult. In another embodiment, the ghrelin agonist useful to ameliorate a reduction in growth, a reduction in growth rate, a reduction in body weight, a reduction in lean body mass, a reduction in IGF-1 levels and/or a reduction in bone mass is [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2) or other suitable ghrelin agonist.

"In yet another embodiment, the reduction in growth, growth rate, body weight, lean body mass, IGF-1 levels and/or bone mass is a result of the administration of dexamethasone.

"In another aspect of said first embodiment, the administration includes, but is not limited to, subcutaneous, intramuscular, intranasal, intraperitoneal, and intravenous administration.

"In a second embodiment, the invention provides a method allowing for the long term administration of therapeutic doses of glucocorticoids to treat a disease or condition, comprising alleviating the catabolic effects of the administration of said long term therapeutic doses of glucocorticoids by the administration of a ghrelin agonist. In one aspect of said second embodiment, the ghrelin agonist is [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2) or other suitable ghrelin agonist. In yet another aspect of said second embodiment, the glucocorticoid is dexamethasone. The individual receiving the method of the invention to alleviate the catabolic effects of long term administration of therapeutic doses of glucocorticoids, such as dexamethasone, by the administration of a ghrelin agonist, such as [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2) or other suitable ghrelin agonist, is a child or an adult.

"In another aspect of said second embodiment, the invention provides a method allowing for the long term administration of therapeutic doses of glucocorticoids to a child to treat respiratory distress of prematurity, comprising alleviating the catabolic effects of the administration of said long term therapeutic doses of glucocorticoids by the administration of a ghrelin agonist. In another aspect of the foregoing, the ghrelin agonist is [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2) or other suitable ghrelin agonist. In yet another aspect of the foregoing, the glucocorticoid is dexamethasone.

"In yet another aspect of said second embodiment, the invention provides a method allowing for the long term administration of therapeutic doses of glucocorticoids to treat asthma, comprising alleviating the catabolic effects of the administration of said long term therapeutic doses of glucocorticoids by the administration of a ghrelin agonist. In another aspect of the foregoing, the ghrelin agonist is [Aib.sup.2, Glu.sup.3(NH-hexyl)]hGhrelin(1-28)-NH.sub.2 (SEQ ID NO:2) or other suitable ghrelin agonist. In yet another aspect of the foregoing, the glucocorticoid is dexamethasone. The individual receiving the method of the invention allowing the long term administration of therapeutic doses of glucocorticoids to treat asthma may be a child or an adult.

"In yet another embodiment, the invention provides a method allowing for the long term administration of therapeutic doses of glucocorticoids to treat a disease or condition, comprising alleviating the catabolic effects of the administration of said long term therapeutic doses of glucocorticoids by the administration of a ghrelin agonist wherein the administration includes, but is not limited to, intramuscular, intranasal, intraperitoneal, and intravenous administration."

For more information, see this patent: Tulipano, Giovanni; Giustina, Andrea; Dong, Zheng Xin; Culler, Michael DeWitt. Use of a Ghrelin Agonist to Improve the Catabolic Effects of Glucocorticoid Treatment. U.S. Patent Number 8741835, filed November 2, 2011, and published online on June 3, 2014. Patent URL: http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=8741835.PN.&OS=PN/8741835RS=PN/8741835

Keywords for this news article include: Drugs, Asthma, Wellness, Metabolism, Pediatrics, Chemotherapy, Therapeutics, Bone Research, Glucocorticoids, Growth Hormones, Peptide Hormones, Bronchial Diseases, Cushing's Syndrome, Ipsen Pharma S.A.S., Adrenal Gland Diseases, Immune System Diseases, Adrenal Cortex Hormones, Obstructive Lung Diseases.

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Source: Clinical Trials Week