Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEUTICAL COMPOSITIONS COMPRISING UNACYLATED GHRELIN
AND THERAPEUTICAL USES THEREOF
FIELD OF THE INVENTION
This invention relates new compositions comprising unacylated ghrelin and
their therapeutical uses therefor.
BACKGROUND OF THE INVENTION
Ghrelin is a recently discovered gastric hormone of 28 amino acids showing a
unique structure with an n-octanoyl ester at its third serine residue (Kojima
M et al.
Nature 1999; 402(6762):656-660). Though many synthetic peptidyl and
nonpeptidyl
growth hormone (GH) secretagogues (GHS) were identified as ligands of GHS-R,
ghrelin is shown to be a physiological ligand for the GHS-R. Ghrelin
powerfully
stimulates GH secretion through its interaction with GHS-R both in animals and
in
humans (Ukkola, 0 et al., 2002 Ann. Med. 34:102-108). The GH-releasing
activity of
ghrelin is mediated by activation of GHS-R at the pituitary and, mainly, at
the
hypothalamic level (Kojima M et al. Nature 1999; 402(6762):656-660) likely by
enhancing the activity of growth hormone releasing hormone (GHRH)-secreting
neurons and, concomitantly, acting as a functional somatostatin (SS)
antagonist
(Ghigo E et al. Eur J Endocrinol 1997; 136(5):445-460). Other mechanisms have
been
postulated recently as well (Ahnfelt-Ronne I et al. Endocrine 2001; 14(1):133-
135).
The interplay among various factors leading to GH secretion is depicted in
Fig. 1.
The GHS-R and its subtypes are not restricted to the hypothalamus-pituitary
unit but are present also in other central and peripheral tissues (Papotti M
et al. J Clin
Endocrinol Metab 2000; 85(10):3803-3807) and the physiological actions of
ghrelin, as
well as those of synthetic GHS are not restricted to GH secretion. In fact,
ghrelin
stimulates lactotroph and corticotroph hormone secretion, has orexigenic and
cardiovascular actions, shows anti proliferative effects on thyroid and
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breast tumors and regulates gastric motility and acid secretion through
vagal mediation (Ukkola, 0 et al., 2002, Ann. Med. 34:102-108).
In humans, fasting leads to elevated serum GH concentrations.
Traditionally, changes in hypothalamic GHRH and somatostatin have been
considered as the main mechanisms, which induce elevations in GH
secretion during fasting. As ghrelin administration in man also stimulates
GH release, and serum ghrelin concentrations are elevated during fasting,
increased ghrelin actions might be another mechanism whereby fasting
results in the stimulation of GH release.
Although ghrelin is likely to regulate pituitary GH secretion in
interplay with GHRH and SS, GHS receptors have also been identified on
hypothalamic neurons and in the brainstem (Nakazato M et al. Nature
2001; 409(6817):194-198). Apart from potential paracrine effects, ghrelin
may thus offer an endocrine link between the stomach, hypothalamus and
pituitary, suggesting an involvement in the regulation of energy balance.
Tschop et al. have shown that daily peripheral administration of ghrelin in
mice and rats caused weight gain by reducing fat utilization (Tschop M et
al. Nature 2000; 19; 407(6806):908-913). Intracerebroventricular
administration of ghrelin generated a dosedependent increase in food
intake and body weight. Rat serum ghrelin concentrations increased by
fasting and decreased by re-feeding or oral glucose administration, but not
by water ingestion. Apparently ghrelin, in addition to its role in regulating
GH secretion, signals the hypothalamus when an increase in metabolic
efficiency is necessary (Tschop M et al. Nature 2000; 19; 407(6806):908-
913; Muller AF et al. Clin Endocrinol (Oxf) 2001; 55(4):461-467).
Studies by Kojima and others have shown that unacylated
ghrelin (UAG) has no' affinity to the known GHS-R (GHS-Rla receptor),
which is responsible for GH release from the pituitary gland (Kojima M et
al. Nature 1999; 402(6762):656-660). This was confirmed later by
Bednarek MA et al (Bednarek MA et al, J. Med Chem. 2000, 43:4370-
4376), who showed that unacylated ghrelin could not be a physiological
ligand of the GHS-Rla receptor (IC50 > 10,000 nM), since it poorly
activated GHS-Rla at micromolar concentrations; large hydrophobic acyl
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group is obligatory at position 3 of ghrelin for its biological response on GH
secretion.
The PCT application, WO 01/87335A2, discloses methods of selectively
inhibiting ghrelin actions including those on obesity using growth hormone
secretagogue receptor antagonists and ghrelin neutralizing reagents. The
ghrelin
neutralizing reagents are antibodies, single chain antibodies, antibody
fragments, or
antibody-based constructs.
Specific binding of acylated ghrelin can be found in many peripheral tissues
(Papotti M et al. J Clin Endocrinol Metab 2000; 85(10):3803-3807). In these
tissues,
no mRNA expression of the GHS- R1a receptor could be found, indicating that
other
1o receptor (sub)types of receptors that can bind GHS would be responsible for
this
specific binding. These novel receptor/s may mediate ghrelin's peripheral
actions
which are, as shown in this invention, efficiently antagonized by unacylated
ghrelin.
It would be highly desirable to be provided with pharmaceutical compositions
of
nonacylated ghrelin for glycemic control in certain metabolic diseases.
SUMMARY OF THE INVENTION
According to one aspect, the present invention relates to the use of an agent
selected from the group consisting of (a) unacylated ghrelin; (b) the
unacylated ghrelin
of (a) having one or more conservative amino acid substitutions; and (c)
pharmaceutically acceptable salts of (a) or (b), for treatment of insulin
resistance in a
subject.
According to another aspect, the present invention relates to the use of an
agent selected from the group consisting of (a) unacylated ghrelin; (b) the
unacylated
ghrelin of (a) having one or more conservative amino acid substitutions; and
(c)
pharmaceutically acceptable salts of (a) or (b), in the preparation of a
medicament for
treatment of insulin resistance in a subject.
According to yet a further aspect, the present invention relates to a
composition
for treating insulin resistance in a subject, comprising an agent selected
from the
group consisting of (a) unacylated ghrelin; (b) the unacylated ghrelin of (a)
having one
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or more conservative amino acid substitutions; and (c) pharmaceutically
acceptable
salts of (a) or (b), together with a suitable pharmaceutical carrier.
In accordance with the present invention there is provided a composition for
preventing and/or reducing postprandial induction of insulin resistance
comprising a
therapeutical effective amount of at least one of unacylated ghrelin, an
analog thereof
and a pharmaceutical acceptable salt thereof in association with a
pharmaceutical
acceptable carrier.
The composition in accordance with a preferred embodiment of the present
invention, wherein the unacylated ghrelin is having an amino acid as set forth
in SEQ
1o ID NO: 1.
In accordance with the present invention, there is provided a method for
reducing postprandial induction of insulin resistance in a patient comprising
the step of
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administering a therapeutical effective amount of the composition of the
present
invention to the patient.
The method in accordance with a preferred embodiment of the present
invention, wherein the administration is through a route selected
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from the group consisting of intravenous, subcutaneous, transdermal, oral,
buccal, sublingual, nasal and by inhalation.
The method in accordance with a preferred embodiment of the
present invention, wherein the composition is administered in a dose
varying from about 0,001 pg/kg to 10,0 g/kg, more preferably 1 g/kg to 1
mg/kg.
In accordance with the present invention, there is provided the
use of the composition of the present invention for reducing postprandial
induction of insulin resistance in a patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for reducing postprandial induction of insulin resistance in a
patient.
In accordance with the present invention, there is provided a
composition for preventing and/or reducing dawn phenomenon in type I
diabetes patient comprising a therapeutically effective amount of at least
one of unacylated ghrelin, an analog thereof and a pharmaceutically
acceptable salt thereof in association with a pharmaceutically acceptable
carrier.
In accordance with the present invention, there is provided a
method for preventing and/or reducing dawn phenomenon in type I
diabetes patient comprising the step of administering a therapeutically
effective amount of the composition of the present invention to the patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for preventing and/or
reducing dawn phenomenon in type I diabetes patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for preventing and/or reducing dawn phenomenon in type I
diabetes patient.
In accordance with the present invention, there is provided a
composition for reducing body weight increased in a patient suffering from
at least one of type II diabetes and syndrome X comprising a
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therapeutically effective amount of at least one of unacylated ghrelin, an
analog thereof, and a pharmaceutically acceptable salt thereof in
association with a pharmaceutically acceptable carrier.
The composition in accordance with a preferred embodiment of
the present invention, wherein the patient is treated with oral antidiabetic
drugs.
In accordance with the present invention, there is provided a
method for reducing a body weight increased encountered by a patient
suffering from at least one of type II diabetes and syndrome X comprising
the step of administering a therapeutically effective amount of the
composition of the present invention.
In accordance with the present invention, there is provided the
use of the composition of the present invention for reducing a body weight
increased encountered by a patient suffering from at least one of type II
diabetes and syndrome X.
In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for reducing a body weight increased encountered by a
patient suffering from at least one of type II diabetes and syndrome X.
In accordance with the present invention, there is provided a
composition for facilitating treatment of an insulin-resistant patient
comprising a therapeutically effective amount of at least one of unacylated
ghrelin, an analog thereof and a pharmaceutically acceptable salt thereof
in association with a pharmaceutically acceptable carrier.
In accordance with the present invention, there is provided a
method for facilitating the treatment of an insulin-resistant patient
comprising the step of administering a therapeutically effective amount of
the composition of the present invention to the patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for facilitating the treatment
of an insulin-resistant patient.
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In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for facilitating treatment of insulin-resistant patient.
In accordance with the present invention, there is provided a
composition for decreasing fat mass in a growth hormone-deficient patient
comprising a therapeutically effective amount of at least one of unacylated
ghrelin, an analog thereof and a pharmaceutically acceptable salt thereof
in association with a pharmaceutically acceptable carrier.
In accordance with the present invention, there is provided a
method for decreasing fat mass in a growth hormone-deficient patient
comprising the step of administering a therapeutically effective amount of
the composition of the present invention to the patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for decreasing fat mass in
a growth hormone-deficient patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for decreasing fat mass in a growth hormone-deficient patient.
In accordance with the present invention, there is provided a
composition for decreasing fat mass in an ageing patient having a high
body mass index comprising a therapeutically effective amount of at least
one of unacylated ghrelin, an analog thereof and a pharmaceutically
acceptable salt thereof in association with a pharmaceutically acceptable
carrier.
In accordance with the present invention, there is provided a
method for decreasing fat mass in an ageing patient having a high body
mass index comprising the step of administering a therapeutically effective
amount of the composition of the present invention to the patient.
In accordance with the present invention, there is provided the
use of the composition of the present invention for decreasing fat mass in
an ageing patient having a high body mass index.
In accordance with the present invention, there is. provided the
use of the composition of the present invention for the preparation of a
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medicament for decreasing fat mass in an ageing patient having a high
body mass index.
In accordance with the present invention, there is provided a
composition for preventing and/or reducing insulin resistance in a patient
comprising a therapeutically effective amount of at least one of unacylated
ghrelin, an analog thereof and a pharmaceutically acceptable salt thereof
in association with a pharmaceutically acceptable carrier.
In accordance with the present invention, there is provided a
method for preventing and/or reducing insulin resistance in a patient in
severe catabolism comprising the step of administering to said patient a
therapeutically effective amount of the composition of the present
invention.
In accordance with the present invention, there is provided the
use of the composition of the present invention for preventing and/or
reducing insulin resistance in a patient in severe catabolism.
In accordance with the present invention, there is provided the
use of the composition of the present invention for the preparation of a
medicament for preventing and/or reducing insulin resistance in a patient in
severe catabolism.
In the present application, the terms "Ghrelin" and "Acylated
ghrelin" are used interchangeably and are intended to mean the same.
For the purpose of the present invention the following terms are
defined below.
The term "Unacylated ghrelin" is intended to mean peptides that
contain the amino acid sequence specified in Seq ID No. 1. Naturally-
occuring variations of unacylated ghrelin include peptides that contain
substitutions, additions or deletions of one or more amino acids which
result due to discrete changes in the nucleotide sequence of the encoding
ghrelin gene or its alleles thereof or due to alternative splicing of the
transcribed RNA. It is understood that the said changes do not
substantially affect the antagonistic properties, pharmacological and
biological characteristics of unacylated ghrelin variant. Those peptides may
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be in the form of salts, particularly the acidic functions of the molecule may
be replaced by a salt derivative thereof such as a trifuoroacetate salt.
The term "Analogue of unacylated ghrelin" refers to both
structural and functional analogues of unacylated ghrelin which are
capable of replacing unacylated ghrelin in antagonizing the peripheral
actions of ghrelin. Simple structural analogues comprise peptides showing
homology with unacylated ghrelin as set forth in SEQ ID No. 1 or a
fragment thereof. For example, an isoform of ghrelin-28 (SEQ ID No. 1),
des Gln-14 Ghrelin (a 27 amino acid peptide possessing serine 3
modification by n-octanoic acid) is shown to be present in stomach; it is
functionally identical to ghrelin in that it binds to GHS-Rla with similar
binding affinity, elicits Ca 2+ fluxes in cloned cells and induces GH
secretion
with similar potency as Ghrelin-28.
The term "Homology" refers to sequence similarity between
two peptides while retaining an equivalent biological activity. Homology
can be determined by comparing each position in the aligned
sequences. A degree of homology between amino acid sequences is a
function of the number of identical or matching amino acids at positions
shared by the sequences so that an "homologous sequence" refers to a
sequence sharing homology and an equivalent function or biological
activity.
It is known that des-Gln14-ghrelin is a structural analogue and a
functional analogue of ghrelin; as such, unacylated des-glnl4-ghrelin could
potentially antagonize effects of ghrelin and des-Glnl4-ghrelin on
peripheral metabolism involving insulin secretion and glycemic control.
Functional analogues of unacylated ghrelin dispite their diversity
have the common interesting property of being able to fully replace
unacylated ghrelin in one or more biological activities exhibited by
unacylated ghrelin. For example, these biological activities of unacylated
ghrelin may include, binding to a specific receptor, altering the signals
arising from the activation of said receptor, modulating the functional
consequences of activation of said receptor.
Functional analogues of unacylated ghrelin, as well as those of
unacylated des-Glnl4-ghrelin, are able to produce the biological effects of
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unacylated ghrelin in antagonizing the peripheral metabolic actions of ghrelin
such as
those on insulin levels and glycemic control, as described in the present
application,
hence such functional analogues will be usefull for realizing therapeutic
benefits in
medical conditions involving GH- deficient states.
Conservative substitutions of one or more amino acids in the primary sequence
of unacylated ghrelin may provide structural analogues of the peptide. In
order to
derive more potent analogues, it is customary to use alanine scans, selective
substitutions with D-amino acid or synthetic amino acids, truncation of the
peptide
sequence in order to find a "functional core" of the peptide, covalent
addition of
molecules to improve the properties of the peptide such as its serum
stability, in vivo
half life, potency, hydrophilicity or hydrophobicity and immunogenicity.
General methods and synthetic strategies used in providing functional and
structural analogues of peptides is described in publications such as "Solid
phase
peptide synthesis" by Stewart and Young, W. H. Freeman & Co., San Francisco,
1969
and Erickson and Merrifield, "The Proteins" Vol. 2, p. 255 et seq. (Ed.
Neurath and
Hill), Academic Press, New York, 1976.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 illustrates the interplay among various factors leading to GH
secretion;
Fig. 2A illustrates glucose concentration over time in absence and in presence
of the GH receptor antagonist pegvisomant upon administration of GHRP-6;
Fig. 2B illustrates insulin concentration over time in absence and in presence
of
the GH receptor antagonist pegvisomant upon administration of GHRP-6;
Fig. 3 illustrates the serum Ghrelin, and GH concentrations (Solid line:
ghrelin
levels ; dotted line : GH levels) during fasting for three days and after a
bolus injection
of GHRP-6 on day 4.;
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Fig. 4A illustrates insulin variation over time in a patient having received a
single intravenous administration of human ghrelin (solid dots) or placebo
(open dots);
Fig. 4B illustrates glucose variation over time in a patient having received a
single intravenous administration of human ghrelin (solid dots) or placebo
(open dots);
Fig. 5A illustrates insulin level over time in a patient having been
administered
with ghrelin, desoct-ghrelin or ghrelin and desoct-ghrelin; and
Fig. 5B illustrates glucose level over time in a patient having been
administered
with ghrelin, desoct-ghrelin or ghrelin and desoct-ghrelin.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided pharmaceutical
compositions for acting on insulin levels and glycemia in metabolic diseases.
It has recently been demonstrated that the growth hormone secretagogue,
GHRP-6, has direct and non-GH dependent actions on metabolism (Muller AF et
al. J
Clin Endocrinol Metab 2001; 86(2):590-593). It is shown in the present
application that
in normal human beings, preprandial GHS administration (1 pg/Kg i.v.) induces
a
postprandial increase in serum glucose levels, but only in the presence of the
GH
receptor antagonist pegvisomant (Fig. 2A).
Moreover, this is accompanied by an impressive increase in serum insulin
concentrations (indicating insulin resistance; Fig. 2B), and a rapid decrease
of free
fatty acids. These GHS-mediated changes indicate that when GH bioactivity is
lowered (as seen in GH deficient, ageing. obese and diabetic individuals), GHS
can
induce potent changes in metabolic control, which are characteristic of the
"metabolic
syndrome X". Because in this study GH-action was blocked by pegvisomant, these
GHS-mediated metabolic changes on the "gastro-entero-hepatic axis" must be
direct
and non-pituitary mediated. Supporting this hypothesis, daily ghrelin
administration in
rodents for only several days, indeed induces an obese state, again indicating
that
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these GHS-mediated effects on metabolism are powerful and clinically
relevant.
The data presented in the present application indicate that
GHS-mediated effects are involved in the induction of the metabolic
alterations, as well as subsequent changes in body composition, which
are characteristic for the insulin resistance syndrome (metabolic
syndrome), as observed in GH deficiency, but also during normal
ageing, obesity and diabetes.
In order to understand the diurnal rhythms of ghrelin and GH
secretion during fasting, a study was conducted on 10 healthy human
volunteers with normal body mass index. Fig. 3 shows the serum
Ghrelin, and GH concentrations (Solid line: ghrelin levels; dotted line:
GH levels). during fasting for three days and after a bolus 'injection of
GHRP-6 on day 4. Fasting rapidly induces a diurnal ghrelin rhythm that
is followed by a similar GH rhythm. Administration of 1 pg/kg of GHRP-
6 on the 3rd day of fasting attenuated peak ghrelin levels in the
afternoon. This clearly shows that fasting induces an acute and distinct
diurnal rhythm in systemic ghrelin concentrations that is not present in
the fed state. These changes in serum ghrelin levels during fasting are
followed by similar changes in serum GH concentrations, indicating that
ghrelin is the driving force of increased GH secretion during fasting.
This phenomenon cannot be explained by changes in insulin, glucose
or free fatty acid levels. Thus it appears that the metabolic effects of
ghrelin are distinct from its effects on GH secretion.
By the use of the GH receptor antagonist pegvisomant,
indirect evidence was provided that these changes in serum ghrelin
levels are not regulated by the GH receptor. Finally, it was shown that
administration of the synthetic GHS, GHRP-6, produced a decrease, in
peak ghrelin levels, but this effect was only observed after several
hours, indicating the existence of a long-loop feedback system of GHS's
on ghrelin secretion.
In order to elucidate the metabolic effects of ghrelin, a study
was performed on 11 healthy young male volunteers in whom glucose
and insulin levels were measured after a single intravenous
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administration of human ghrelin (1.0 pg/kg i.v. at 0') or placebo. Fig. 4
shows that ghrelin produced acute decrease in insulin [ mean ( SEM)
A insulin] (top panel) and elevation in glucose [A mean ( SEM)
glucose] levels (bottom panel) (solid dots: ghrelin; open dots: placebo).
This data clearly shows that ghrelin has distinct and immediate effects
on glucose and insulin, two important determinants of metabolism in
humans (Broglio F et al. Journal of Clinical Endocrinology & Metabolism
2001; 86(10):5083-5086).
Thus the data reported in the present application, indicate that
ghrelin has important physiological actions, not only on GH secretion but
also on the modification of glucose and insulin concentrations in living
(human or animal) beings.
Ghrelin appears to have a role in managing not only GH
secretion but also the metabolic response to starvation by modulating
insulin secretion and glucose metabolism.
In an analysis of a study in normal human volunteers (n = 6),
it was surprisingly observed that the administration of unacylated
ghrelin (1 pg/kg iv at 0 min) totally prevented the ghrelin (1 pg/kg iv at 0
min)-induced increase in glucose and decrease in insulin levels. The
lots of unacylated ghrelin used in this study had the following
specifications: tifluoroacetate salt of unacylated ghrelin, 95.1% pure as
judged by HPLC, Mass: 3244.7 amu, and the peptide has amino acid
composition representative of the sequence listed in SEQ ID. NO:. 1.
Figs. 5A-5B show the mean ( SEM) A insulin (top panel) and A
glucose (bottom panel) levels after a single intravenous administration of
human acylated ghrelin (1.0 pg/kg i.v. at 0'), human des-acylated ghrelin
(1.0 pg/kg i.v. at 0') or the co-administration of both. Thus it appears that
unacylated ghrelin is acting as a functional antagonist of the peripheral
actions of ghrelin. This last result was surprising and unexpected, since
unacylated ghrelin has never been shown previously to antagonize or
inhibit the biological effects of acylated ghrelin. Most of ghrelin actions,
especially on GH secretion were thought to be mediated by GHS-Rla
receptor for which unacylated ghrelin has little affinity. In fact,
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unacylated ghrelin has so far been considered as a peptide without any
biological activity.
Hence in this invention, it was shown that unacylated ghrelin acts
as a functional antagonist to inhibit important peripheral actions of acylated
ghrelin on two crucial parameters of metabolism-insulin and glucose. To
provide therapeutic benefits to patients in various states of insulin
resistance, preferably those associated with low GH action and/or
increased acylated ghrelin secretion, unacylated ghrelin (NH2-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 : SEQ ID NO. 1) or its analogue may be
administred in a pharmaceutical composition intravenously,
subcutaneously, transdermally, orally or by inhalation. Preparation of
pharmaceutical compositions suitable for intravenous, subcutaneous,
transdermal, oral, buccal, sublingual and pulmonary delivery are known to
people skilled in the arts.
It is understood that the data reported in the present
specification are only given to illustrate the invention and may not be
regarded as constituting a limitation thereof.
While the invention has been described in connection with
specific embodiments thereof, it will be understood that it is capable of
further modifications and this application is intended to cover any
variations, uses, or adaptations of the invention following, in general, the
principles of the invention and including such departures from the present
disclosure as come within known or customary practice within the art to
which the invention pertains and as may be applied to the essential
features hereinbefore set forth, and as follows in the scope of the
appended claims.
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SEQUENCE LISTING
<110> Theratechnologies Inc.
Ghigo, Ezio
Van der Lely, Aart Jan
<120> Pharmaceutical compositions comprising unacylated ghrelin and
therapeutical uses thereof
<130> 85795-11
<150> CA 2,365,704
<151> 2001-12-18
<150> PCT/CA02/01964
<151> 2002-12-18
<160> 1
<170> Patentln version 3.2
<210> 1
<211> 28
<212> PRT
<213> Artificial
<220>
<223> synthetic polypeptide: unacylated ghrelin
<400> 1
Gly Ser Ser Phe Leu Ser Pro Glu His Gln Arg Val Gln Gln Arg Lys
1 5 10 15
Glu Ser Lys Lys Pro Pro Ala Lys Leu Gln Pro Arg
20 25
