U.S. patent application number 10/359324 was filed with the patent office on 2003-10-23 for use of glp-1 compound for treatment of critically ill patients.
Invention is credited to Hansen, Kristian Tage, Knudsen, Lotte Bjerre, Selmer, Johan.
Application Number | 20030199445 10/359324 |
Document ID | / |
Family ID | 29219220 |
Filed Date | 2003-10-23 |
United States Patent
Application |
20030199445 |
Kind Code |
A1 |
Knudsen, Lotte Bjerre ; et
al. |
October 23, 2003 |
Use of GLP-1 compound for treatment of critically ill patients
Abstract
Use of medicament for life saving treatment of critically ill
patients and method of treatment. The medicament comprises a GLP-1
compound which effectively controls the blood glucose level.
Inventors: |
Knudsen, Lotte Bjerre;
(Valby, DK) ; Selmer, Johan; (Farum, DK) ;
Hansen, Kristian Tage; (Slangerup, DK) |
Correspondence
Address: |
Reza Green, Esq.,
Novo Nordisk Pharmaceuticals, Inc.
100 College Road West
Princeton
NJ
08540
US
|
Family ID: |
29219220 |
Appl. No.: |
10/359324 |
Filed: |
February 6, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60359834 |
Feb 26, 2002 |
|
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|
Current U.S.
Class: |
514/5.9 ;
514/11.7; 514/6.7; 514/6.8; 514/6.9; 514/7.2; 514/7.5 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 25/00 20180101; A61P 3/10 20180101; A61P 17/02 20180101; A61P
29/00 20180101; A61P 3/08 20180101; A61P 7/12 20180101; A61K 38/26
20130101 |
Class at
Publication: |
514/12 |
International
Class: |
A61K 038/26 |
Foreign Application Data
Date |
Code |
Application Number |
Feb 7, 2002 |
DK |
PA 2002 00184 |
Claims
1. Use of a GLP-1 compound for the manufacture of a medicament for
treatment or cure of a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient.
2. The use according to claim 1, wherein the treatment or cure
increases the survival rate of critically ill patients and/or CIPNP
patients and/or potential CIPNP patients.
3. The use according to claim 1, wherein the treatment or cure
reduces the time where a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient is hospitalized.
4. The use according to claim 3, wherein the patient is
hospitalized in an ICU.
5. Use of a GLP-1 compound for the manufacture of a medicament for
preventing that a patient becomes critically ill or develops
CIPNP.
6. Use of a GLP-1 compound for the manufacture of a medicament for
prevention, treatment or cure of SIRS in a patient.
7. Use of a GLP-1 compound for the manufacture of a medicament for
preventing or reducing the likelihood of a patient suffering from
bacteraemia, septicaemia and/or septic shock during
hospitalization.
8. The use according to claim 7, where the hospitalization is in an
ICU.
9. The use according to any one of claims 7-8, wherein the patient
is selected from a critically ill patient, a CIPNP patient, a
potential CIPNP patient, a SIRS patient and a potential SIRS
patient.
10. Use of a GLP-1 compound for manufacturing a medicament for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potential CIPNP patient acquires an
infectious disease.
11. The use according to claim 10, wherein the infectious disease
has a mortal outcome.
12. Use of a GLP-1 compound for manufacturing a medicament for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potential CIPNP patient dies due to
an infection.
13. Use of a GLP-1 compound for manufacturing a medicament for
reducing the rate of infection with mortal outcome in critically
ill patients and/or CIPNP patients and/or potential CIPNP patients
in an ICU.
14. The use according to claim 1, wherein the treatment or cure
reduces mortality, duration of hospitalization, frequency of
bacteraemia, frequency of septicaemia, frequency of septic shock,
need for dialysis, and/or need for ventilatory support in said
patient.
15. The use of a GLP-1 compound for the manufacture of a medicament
to treat a critically ill patient and/or a CIPNP-patient and/or a
potential CIPNP-patient so that the patient is no longer in need of
vital organ system support or to treat a critically ill patient
and/or a CIPNP-patient and/or a potential CIPNP-patient so that it
is considered sufficient for the patient to receive at least about
two third of the caloric need through the normal enteral route to
reduce the risk or likelihood from multiple organ failure, to
reduce the risk or likelihood from multiple organ failure with a
proven septic focus on post-mortem examination, to reduce
mortality, for example, in-hospital mortality, to reduce the use of
mechanical ventilatory support, to reduce the likelihood of renal
replacement therapy and/or renal failure, to reduce the likelihood
of disturbed kidney function parameters, to reduce the likelihood
of hyperbilirubinemia, to reduce the likelihood for blood stream
infections, to reduce the likelihood of disturbance in markers of
inflammations and/or inflammatory responses, to reduce the use of
antibiotics, to reduce the amount of red cell transfusion, or to
reduce stress induced hyperglycaemia, or to reduce the likelihood
of the critically ill patient and/or the CIPNP-patient and/or the
potential CIPNP-patient having repetitive positive EMGs, or to
prevent or reduce the amount of ultimately futile intensive care to
a critically ill patient and/or a CIPNP-patient and/or a potential
CIPNP-patient, or to protect a critically ill patient and/or a
CIPNP-patient and/or a potential CIPNP-patient from cholestasis, or
to reduce the need for invasive treatment in a critically ill
patient and/or a CIPNP-patient and/or a potential
CIPNP-patient.
16. The use according to any one of claims 1-15, wherein the GLP-1
compound is GLP-1(7-36)-amide, GLP-1(7-37), or an analogue thereof
or a derivative thereof.
17. The use according to claim 16, wherein the GLP-1 compound is a
derivative of GLP-1(7-36)-amide or GLP-1(7-37) which comprises a
lipophilic substituent.
18. The use according to any one of claims 16-17, wherein the GLP-1
compound is Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..al-
pha.-hexadecanoyl)))-GLP-1(7-37).
19. The use according to claim 16, wherein the GLP-1 compound is
selected from the group consisting of Gly.sup.8-GLP-1(7-36)-amide,
Gly.sup.8-GLP-1(7-37), Val.sup.8-GLP-1(7-36)-amide,
Val.sup.8-GLP-1(7-37), Val.sup.8Asp.sup.22-GLP-1(7-36)-amide,
Val.sup.8Asp.sup.22-GLP-1(7-37),
Val.sup.8Glu.sup.22-GLP-1(7-36)-amide,
Val.sup.8Glu.sup.22-GLP-1(7-37),
Val.sup.8Lys.sup.22-GLP-1(7-36)-amide,
Val.sup.8Lys.sup.22-GLP-1(7-37,
Val.sup.8Arg.sup.22-GLP-1(7-36)-amide,
Val.sup.8Arg.sup.22-GLP-1(7-37),
Val.sup.8His.sup.22-GLP-1-36)-amide,
Val.sup.8His.sup.22-GLP-1(7-37), analogues thereof and derivatives
thereof.
20. The use according to claim 16, wherein the GLP-1 compound is a
stable GLP-1 analog/derivative.
21. The use according to any one of claims 1-15, wherein the GLP-1
compound is exendin-4 or an analogue thereof or a derivative
thereof.
22. The use according to any one of claims 1-15 and 21, wherein the
GLP-1 compound is a stable exendin-4 analog/derivative.
23. The use according to any one of claims 1-22, wherein the GLP-1
compound is to be administered parenterally.
24. The use according to claim 23, wherein the GLP-1 compound is
administered by injection.
25. The use according to claim 23, wherein the GLP-1 compound is
administered by infusion or drip.
26. The use according to any one of claims 23-25, wherein the
dosage of GLP-1 compound is from about 0.5 .mu.g/kg/day to about 20
.mu.g/kg/day.
27. The use according to any one of claims 23-25, wherein the
dosage of GLP-1 compound is from about 0.1 .mu.g/kg/day to about 2
.mu.g/kg/day.
28. The use according to any one of claims 1-25, wherein the GLP-1
compound is used such that the blood glucose level is kept below an
upper limit which is about 110 mg/dL, about 120 mg/dL or about 130
mg/dL.
29. The use according to any one of claims 1-25, wherein the GLP-1
compound is used such that the blood glucose level is kept within a
range where the lower limit is about 60 mg/dL, about 70 mg/dL or
about 80 mg/dL and the upper limit is about 110 mg/dL, about 120
mg/dL or about 130 mg/dL, preferably in the range of 80 to about
110 mg/dL.
30. The use according to any one of claims 1-25, wherein the GLP-1
compound is used such that the blood glucose level is kept within a
range from about 60 mg/dL to about 130 mg/dL, preferably from about
70 mg/dL to about 120 mg/dL, more preferred from about 80 mg/dL to
about 110 mg/dL.
31. The use according to any one of claims 28-30, wherein the blood
glucose level is kept within the specified range for a period of
more than about 8 hours, preferably for more than about 24 hours,
more preferred for more than about 2 days, even more preferred for
more than about 4 days, and even more preferred for more than about
7 days.
32. The use according to any one of claims 1-31, wherein a second
blood glucose regulator is used.
33. The use according to claim 32, wherein the second blood
glucose-regulator is selected from insulin, insulin analogs,
insulin derivatives, insulin secretagogues, insulin compounds that
stimulate signal transduction mediated by an insulin receptor type
tyrosine kinase in a cell, protein-tyrosine phosphatases and Type
II antidiabetica.
34. The use according to claim 32, wherein the second blood glucose
regulator is selected from insulin, an insulin analog, an insulin
derivative, a GLP-1 compound and an orally administered blood
glucose regulator.
35. The use according to any one of claims 32-34, wherein
treatment, curing or prevention is performed by administering an
effective amount of the second blood glucose regulator.
36. The use according to any one of claims 1-35, wherein the
patient is a non-diabetic patient.
37. The use according to any one of claims 1-36, wherein the
patient is a human.
38. The use according to any one of claims 1-37, wherein the
patient is in need of cardiac surgery, cerebral surgery, thoracic
surgery, abdominal surgery, vascular surgery, or transplantation,
or a patient suffering from neurological diseases, cerebral trauma,
respiratory insufficiency, abdominal peritonitis, multiple trauma,
severe burns, or CIPNP.
39. The use according to any one of claims 1-38, wherein the
patient is fed parenterally.
40. The use according to any one of claims 1-39, wherein the
patient receives at least about one third of the caloric need
through the normal enteral route, preferably at least about half of
the caloric need through the normal enteral route, most preferable
at least about two third of the caloric need through the normal
enteric route.
41. The use according to any one of claims 1-40, wherein treatment,
curing or prevention is performed by administering an effective
amount of the GLP-1 compound.
42. Use of a GLP-1 compound for the treatment or cure of critically
ill patients and/or CIPNP patients and/or potential CIPNP
patients.
43. The use according to claim 42, wherein said treatment or cure
comprises a pharmaceutically effective composition comprising the
GLP-1 compound.
44. The use according to any one of claims 42-43, wherein said use
is to attain the clinical benefits mentioned in any one of the
preceding claims.
45. A kit of parts comprising a medicament wherein is a GLP-1
compound and an insert label stating the use of said medicament for
treating critically ill patients within an ICU.
46. A method of marketing a GLP-1 compound, said method comprising
the dissemination of information about the indications, utilities
and benefits of a GLP-1 compound or a pharmaceutical composition
comprising a GLP-1 compound, said indications, utilities, benefits
and GLP-1 compounds being described in the preceding claims.
47. The method according to claim 46, wherein the information is
disseminated by means of printed material, oral presentation or
electromagnetic signals, such as via internet, telephone,
television, radio or computer.
48. The method according to any one of claims 46-47, wherein the
information is disseminated to physicians and/or persons
responsible for health care budgets, preferably to physicians
working in an ICU and persons responsible for an ICU budget.
49. Advertising medium to disseminate information about the
indications, utilities and benefits of a GLP-1 compound or a
pharmaceutical composition comprising a GLP-1 compound, said
indications, utilities, benefits and GLP-1 compounds being
described in the preceding claims.
50. The advertising medium according to claim 49, wherein said
advertising medium is selected from the group consisting of a
brochure, pamphlet, prospectus, videotape, DVD disk and CD
disk.
51. A method for treating a critically ill patient and/or a patient
having critical illness polyneuropathy (CIPNP) and/or a patient
having systemic inflammatory response syndrome (SIRS), said method
comprising administering to said patient a therapeutically
effective amount of a GLP-1 compound.
52. The method according to claim 51, wherein the GLP-1 compound is
GLP-1(7-36)-amide, GLP-1(7-37), or an analogue thereof or a
derivative thereof.
53. The method according to claim 52, wherein the GLP-1 compound is
a derivative of GLP-1(7-36)-amide or GLP-1(7-37) which comprises a
lipophilic substituent.
54. The method according to claim 53, wherein the GLP-1 compound is
Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadec-
anoyl)))-GLP-1(7-37).
55. The method according to claim 52, wherein the GLP-1 compound is
selected from the group consisting of Gly.sup.8-GLP-1(7-36)-amide,
Gly.sup.8-GLP-1(7-37), Val.sup.8-GLP-1(7-36)-amide,
Val.sup.8-GLP-1(7-37), Val.sup.8Asp.sup.22-GLP-1(7-36)-amide,
Val.sup.8Asp.sup.22-GLP-1(7-37),
Val.sup.8.sup.Glu.sup.22-GLP-1(7-36)-ami- de,
Val.sup.8Glu.sup.22-GLP-1(7-37),
Val.sup.8Lys.sup.22-GLP-1(7-36)-amide- ,
Val.sup.8Lys.sup.22-GLP-1(7-37),
Val.sup.8Arg.sup.22-GLP-1(7-36)-amide,
Val.sup.8Arg.sup.22-GLP-1(7-37),
Val.sup.8His.sup.22-GLP-1(7-36)-amide,
Val.sup.8His.sup.22-GLP-1(7-37), and analogues and derivatives
thereof.
56. The method according to claim 51, wherein the GLP-1 compound is
a stable GLP-1 analog/derivative.
57. The method according to claim 51, wherein the GLP-1 compound is
exendin-4 or an analogue thereof or a derivative thereof.
58. The method according to claim 51, wherein the GLP-1 compound is
a stable exendin-4 analog/derivative.
59. The method according to claim 51, wherein the GLP-1 compound is
administered parenterally.
60. The method according to claim 51, wherein the GLP-1 compound is
administered by injection.
61. The method according to claim 51, wherein the GLP-1 compound is
administered by infusion or drip.
62. The method according to claim 51, wherein the GLP-1 compound is
administered at a dosage of from about 0.5 .mu.g/kg/day to about 20
.mu.g/kg/day.
63. The method according to claim 51, wherein the GLP-1 compound is
administered at a dosage of from about 0.1 .mu.g/kg/day to about 2
.mu.g/kg/day.
64. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept below an upper limit of about 110 mg/dL.
65. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept below an upper limit which is about 120 mg/dL.
66. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept below an upper limit which is about 130 mg/dL.
67. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept within a range between about 60 mg/dL and about 130
mg/dL.
68. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept within a range between about 70 mg/dL and about 120
mg/dL.
69. The method according to claim 51, wherein said administration
of the GLP-1 compound results in said patient's blood glucose level
being kept within a range between about 80 mg/dL and about 110
mg/dL.
70. The method according to claim 51, wherein said patient is
further administered a blood glucose regulator.
71. The method according to claim 70, wherein the blood glucose
regulator is selected from the group consisting of insulin, insulin
analogs, insulin derivatives, insulin secretagogues, insulin
compounds that stimulate signal transduction mediated by an insulin
receptor type tyrosine kinase in a cell, protein-tyrosine
phosphatases and Type II antidiabetic compounds.
72. The method according to claim 70, wherein the blood glucose
regulator is selected from the group consisting of insulin, an
insulin analog, an insulin derivative, a second GLP-1 compound and
an orally administered blood glucose regulator.
73. The method according to claim 51, wherein the patient is a
non-diabetic.
74. The method according to claim 51, wherein the patient is a
human.
75. The method according to claim 51, wherein the patient is in
need of a surgery selected from the group consisting of cardiac
surgery, cerebral surgery, thoracic surgery, abdominal surgery,
vascular surgery, and transplantation.
76. The method according to claim 51, wherein the patient is
suffering from a condition selected from the group consisting of
neurological diseases, cerebral trauma, respiratory insufficiency,
abdominal peritonitis, multiple trauma, and severe burns.
77. The method according to claim 51, wherein the patient is fed
parenterally.
78. The method according to claim 51, wherein at least about one
third of said patient's caloric intake is through the normal
enteric route.
79. The method according to claim 51, wherein at least about half
of said patient's caloric intake is through the normal enteric
route.
80. The method according to claim 51, wherein at least about two
third of said patient's caloric intake is through the normal
enteric route.
81. The method according to claim 67, wherein said patient's blood
glucose level is kept within the specified range for a period of
more than about 8 hours.
82. The method according to claim 67, wherein said patient's blood
glucose level is kept within the specified range for a period of
more than about 24 hours.
83. The method according to claim 67, wherein said patient's blood
glucose level is kept within the specified range for a period of
more than about 2 days.
84. The method according to claim 67, wherein said patient's blood
glucose level is kept within the specified range for a period of
more than about 4 days.
85. The method according to claim 67, wherein said patient's blood
glucose level is kept within the specified range for a period of
more than about about 7 days.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under 35 U.S.C. 119 of
Danish application no. PA 2002 00184 filed Feb. 7, 2002 and U.S.
provisional application No. 60/359,834 filed Feb. 26, 2002, the
contents of which are fully incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for prevention,
treatment and/or cure of critically ill patients. More
specifically, the methods and uses of the invention pertains to
administration of a GLP-1 compound or a pharmaceutical medicament
comprising a GLP-1 compound to critically ill patients.
Furthermore, the present invention relates to a method for
marketing GLP-1 compounds and to advertising media used for
disseminating information.
BACKGROUND OF THE INVENTION
[0003] A specific type of polyneuropathy develops in patients that
are treated within an intensive care unit (hereinafter also
designated ICU) for several days to weeks and this for a variety of
primary injuries or illnesses. This polyneuropathy, known as
"Critical Illness Polyneuropathy" (hereinafter also designated
CIPNP) occurs in about 70% of patients who have the systemic
inflammatory response syndrome (SIRS) (Zochodne D W et al. 1987
Polyneuropathy associated with critical illness: a complication of
sepsis and multiple organ failure. Brain, 110: 819-842); (Leijten F
S S & De Weerdt A W 1994 Critical illness polyneuropathy: a
review of the literature, definition and pathophysiology. Clinical
Neurology and Neurosurgery, 96: 10-19). However, clinical signs are
often absent and it remains an acute problem in many ICUs
worldwide. Nonetheless, it is an important clinical entity as it is
a frequent cause of difficulty in weaning patients from the
ventilator and it leads to problems with rehabilitation after the
acute illness has been treated and cured.
[0004] When CIPNP is severe enough, it causes limb weakness and
reduced tendon reflexes. Sensory impairment follows but is
difficult to test in ICU patients. Electrophysiological examination
(EMG) is necessary to establish the diagnosis (Bolton C F. 1999
Acute Weakness. In: Oxford Textbook of Critical Care; Eds. Webb A
R, Shapiro M J, Singer M, Suter P M; Oxford Medical Publications,
Oxford UK; pp. 490-495). This examination will reveal a primary
axonal degeneration of first motor and then sensory fibers. Phrenic
nerves are often involved. Acute and chronic denervation has been
confirmed in muscle biopsies of this condition. If the underlying
condition (sepsis or SIRS) can be successfully treated, recovery
from and/or prevention of the CIPNP can be expected. This will
occur in a matter of weeks in mild cases and in months in more
severe cases. In other words, the presence of CIPNP can delay the
weaning and rehabilitation for weeks or months.
[0005] The pathophysiology of this type of neuropathy remains
unknown (Bolton C F 1996 Sepsis and the systemic inflammatory
response syndrome: neuromuscular manifestations. Crit Care Med. 24:
1408-1416). It has been speculated to be directly related to sepsis
and its mediators. Indeed, cytokines released in sepsis have
histamine-like properties which may increase microvascular
permeability. The resulting endoneural edema could induce hypoxia,
resulting in severe energy deficits and hereby primary axonal
degeneration. Alternatively, it has been suggested that cytokines
may have a direct cytotoxic effect on the neurons. Contributing
factors to disturbed microcirculation are the use of neuromuscular
blocking agents and steroids. Moreover, a role for aminoglucosides
in inducing toxicity and CIPNP has been suggested. However, there
is still no statistical proof for any of these mechanisms in being
a true causal factor in the pathogenesis of CIPNP.
[0006] Polyneuropathy of critical illness was first described in
1985 by three different investigators, one Canadian, one American,
and one French. Until recently there was no effective treatment to
prevent or stop Critical Illness Polyneuropathy. Until recently the
current standard of practice of care, especially of critically ill
patients, was that within the settings of good clinical ICU
practice, blood glucose levels are allowed to increase as high as
to 250 mg/dL or there above. The reason for this permissive
attitude is the thought that high levels of blood glucose are part
of the adaptive stress responses, and thus do not require treatment
unless extremely elevated (Mizock B A. Am J Med 1995; 98: 75-84).
Also, relative hypoglycaemia during stress is thought to be
potentially deleterious for the immune system and for healing
(Mizock B A. Am J Med 1995; 98: 75-84).
[0007] The recent work of G. Van Den Berghe showed that mortality
in an ICU could be reduced by strictly controlling the blood
glucose level with insulin (WO 01/85256). Although insulin is very
effective for treating hyperglycaemia and has widespread
therapeutic applications developed over the past 80 years, insulin
may also produce hypoglycaemic events when administered in high
dosages.
[0008] Human GLP-1 is a 37 amino acid residue peptide originating
from preproglucagon which is synthesised i.a. in the L-cells in the
distal ileum, in the pancreas and in the brain. GLP-1 is an
important gut hormone with regulatory function in glucose
metabolism and gastro-intestinal secretion and metabolism.
Processing of preproglucagon to give GLP-1(7-36)-amide, GLP-1(7-37)
and GLP-2 occurs mainly in the L-cells. The fragments
GLP-1(7-36)-amide and GLP-1(7-37) are both glucose-dependent
insulinotropic agents. In the past decades a number of structural
analogs of GLP-1 were isolated from the venom of the Gila monster
lizards (Heloderma suspectum and Heloderma horridum). Exendin-4 is
a 39 amino acid residue peptide isolated from the venom of
Heloderma horridum, and this peptide shares 52% homology with
GLP-1. Exendin-4 is a potent GLP-1 receptor agonist which has been
shown to stimulate insulin release and ensuing lowering of the
blood glucose level when injected into dogs. The group of
GLP-1(1-37), exendin-4(1-39), certain fragments thereof, analogs
thereof and derivatives thereof, (hereinafter designated GLP-1
compounds) are potent insulinotropic agents. Most importantly the
group of GLP-1(1-37), exendin-4(1-39), insulinotropic fragments
thereof, insulinotropic analogs thereof and insulinotropic
derivatives thereof (hereinafter designated GLP-1 compounds)I are
also glucose-dependent in their action, i.e. they normalize
hyperglycemia but as blood glucose concentration decreases their
activity attenuates so that the risk of hypoglycemic events are
eliminated or greatly reduced as compared to the conventional
treatment with insulin. This lack of severe side effect from
overdosing GLP-1 compounds make them very well suited to the
therapeutic application within ICU. The density of intense
monitoring and multiple treatments of patients in ICU makes it
highly advantageous that the strict control of the blood glucose
level is simple and void of risks for hypoglycaemic events.
SUMMARY OF THE INVENTION
[0009] This invention is based on the discovery that critical
illness in a patient and/or CIPNP can be prevented, treated or
cured, at least to a certain extent, by controlling glucose
metabolism during said critical illness by applying intensive
treatment with a GLP-1 compound.
[0010] Blood glucose level is kept below an upper limit which is
about 110 mg/dL, about 120 mg/dL or about 130 mg/dL. More
specifically, blood glucose level is clamped within a range where
the lower limit can be selected to be about 60, about 70 or about
80 mg/dL and the upper limit can be selected to be about 110, about
120 or about 130 mg/dL, more specifically to the normal range
(i.e., from about 80 to about 110 mg/dL). The skilled art worker,
for example, the physician, will be able to decide exactly which
upper and lower limits to use. Alternatively, the range is from
about 60 to about 130, preferably, from about 70 to about 120, more
preferred, from about 80 to about 110 mg/dL.). The skilled art
worker will be able to determine the dosage of GLP-1 compound
without risking to induce a hypoglycaemic event because GLP-1
compounds have a glucose-dependent action where insulin release is
attenuated at lower blood glucose concentrations.
[0011] One object of the present invention is to provide a
treatment or cure of a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient.
[0012] Another object of the present invention is to increase the
survival rate of critically ill patients and/or CIPNP patients
and/or potential CIPNP patients.
[0013] Another object of the present invention is to provide a
treatment or cure that reduces the time where a critically ill
patient and/or a CIPNP patient and/or a potential CIPNP patient is
hospitalized.
[0014] Another object of the present invention is to prevent that a
patient becomes critically ill or develops CIPNP.
[0015] Another object of the present invention is to prevent, treat
or cure SIRS in a patient.
[0016] Another object of the present invention is to prevent or
reduce the likelihood of a patient suffering from bacteraemia,
septicaemia and/or septic shock during hospitalization.
[0017] Another object of the present invention is to prevent or
reduce the likelihood that a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient acquires an infectious
disease.
[0018] Another object of the present invention is to prevent or
reduce the likelihood that a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient acquires an infectious
disease with a mortal outcome.
[0019] Another object of the present invention is to prevent or
reduce the likelihood that a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient dies due to an
infection.
[0020] Another object of the present invention is to reduce the
rate of infection with mortal outcome in critically ill patients
and/or CIPNP patients and/or potential CIPNP patients in an
ICU.
[0021] Another object of the present invention is to provide a
treatment or cure that reduces mortality, duration of
hospitalization, frequency of bacteraemia, frequency of
septicaemia, frequency of septic shock, need for dialysis, and/or
need for ventilatory support in a critically ill patient and/or a
CIPNP patient and/or a potential CIPNP patient.
[0022] Another object of the present invention is to treat a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient, so that said patient is no longer in need of vital
organ system support.
[0023] Another object of the present invention is to treat a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient, so that it is considered sufficient for said patient
to receive at least about two third of the caloric need through the
normal enteral route.
[0024] Another object of the present invention is to reduce the
risk or likelihood from multiple organ failure in a critically ill
patient and/or a CIPNP patient and/or a potential CIPNP
patient.
[0025] Another object of the present invention is to reduce the
risk or likelihood from multiple organ failure with a proven septic
focus on post-mortem examination in a critically ill patient and/or
a CIPNP patient and/or a potential CIPNP patient.
[0026] Another object of the present invention is to reduce
mortality, for example, in-hospital mortality, in a critically ill
patient and/or in a CIPNP patient and/or a potential CIPNP
patient.
[0027] Another object of the present invention is to reduce
morbidity, for example, in-hospital morbidity, in a critically ill
patient and/or in a CIPNP patient and/or a potential CIPNP
patient.
[0028] Another object of the present invention is to reduce the use
of mechanical ventilatory support to a critically ill patient
and/or to a CIPNP patient and/or a potential CIPNP patient.
[0029] Another object of the present invention is to reduce the
likelihood of renal replacement therapy and/or renal failure in a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient.
[0030] Another object of the present invention is to reduce the
likelihood of disturbed kidney function parameters in a critically
ill patient and/or a CIPNP patient and/or a potential CIPNP
patient.
[0031] Another object of the present invention is to reduce the
likelihood of hyperbilirubinemia in a critically ill patient and/or
a CIPNP patient and/or a potential CIPNP patient.
[0032] Another object of the present invention is to reduce the
likelihood for blood stream infections in a critically ill patient
and/or a CIPNP patient and/or a potential CIPNP patient.
[0033] Another object of the present invention is to reduce the
likelihood of disturbance in markers of inflammations and/or
inflammatory responses in a critically ill patient, and/or a CIPNP
patient and/or a potential CIPNP patient.
[0034] Another object of the present invention is to reduce the use
of antibiotics in a critically ill patient and/or a CIPNP patient
and/or a potential CIPNP patient.
[0035] Another object of the present invention is to reduce the
likelihood of a critically ill patient and/or a CIPNP patient
and/or a potential CIPNP patient having repetitive positive
EMGs.
[0036] Another object of the present invention is to reduce the
amount of red cell transfusion to a critically ill patient and/or a
CIPNP patient and/or a potential CIPNP patient.
[0037] Another object of the present invention is to prevent or
reduce the amount of ultimately futile intensive care to a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient.
[0038] Another object of the present invention is to protect a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient from cholestasis.
[0039] Another object of the present invention is to reduce the
need for invasive treatment in a critically ill patient and/or a
CIPNP patient and/or a potential CIPNP patient.
[0040] In accordance with the present invention GLP-1 compounds are
provided for use in the prevention, treatment or cure of a
critically ill patient and/or a CIPNP patient and/or a potential
CIPNP patient.
[0041] This invention demonstrates that controlling blood glucose
levels within the above range, for example, within normal limits
(about 80 to about 110 mg/dL) in a critically ill patient or in a
chronic ill patient can be used to significantly reduce the
incidence of critical illness in a patient and/or CIPNP and to
lengthen the time free of critical illness in a patient and/or
CIPNP in a patient that do develop this problem.
[0042] The invention provides a use of a GLP-1 compound for
preventing or reducing the likelihood of a patient suffering from
bacteraemia, septicaemia and/or septic shock during
hospitalization.
[0043] The invention also provides a use of a GLP-1 compound for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potentially CIPNP patient acquires
an infectious disease.
[0044] The invention also provides a use of a GLP-1 compound for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potentially CIPNP patient dies due
to an infection.
[0045] The invention also provides a use of a GLP-1 compound for
reducing the rate of infection with mortal outcome in critically
ill patients and/or CIPNP patients and/or potentially CIPNP
patients.
[0046] According to the present invention, blood glucose levels are
controlled by treatment with GLP-1 compounds. However after this
invention, it will be clear for the man skilled in the art that
also other agonists of the GLP-1 receptor, prodrugs thereof and
their physiologically tolerated salts can be used to obtain the
same outcome.
DEFINITIONS
[0047] The term "systemic inflammatory response syndrome (SIRS)",
as used herein refers to the uncontrolled disease process which
ensues an initial insult and which gives rise to a multisystem
disturbance secondary to inflammatory mediators released during
shock.
[0048] The term "sepsis", as used herein refers to "SIRS", as
described above, which is particularly caused by an infectious
insult leading to the initial shock phase.
[0049] The term "mediators of sepsis", as used herein refers to
factors released by inflammatory cells, such as TNFs, interleukins,
bradykinins etc.
[0050] The term "insulin receptor type tyrosine kinase", as used
herein refers to a post-receptor signal transduction pathway
involved in the insulin signaling.
[0051] The term "endoneural edema", as used herein refers to
swelling of the neuronal cells.
[0052] The term "phrenic nerves", as used herein refers to the left
and right nervus phrenicus, innervating the diaphragm.
[0053] The term "GLP-1 compound", as used herein refers to
GLP-1(1-37), exendin-4(1-39), insulinotropic fragments thereof,
insulinotropic analogs thereof and insulinotropic derivatives
thereof. Insulinotropic fragments of GLP-1(1-37) are insulinotropic
peptides for which the entire sequence can be found in the sequence
of GLP-1(1-37) and where at least one terminal amino acid has been
deleted. Examples of insulinotropic fragments of GLP-1(1-37) are
GLP-1(7-37) wherein the amino acid residues in positions 1-6 of
GLP-1(1-37) have been deleted, and GLP-1(7-36) where the amino acid
residues in position 1-6 and 37 of GLP-1(1-37) have been deleted.
Examples of insulinotropic fragments of exendin-4(1-39) are
exendin-4(1-38) and exendin-4(1-31). The insulinotropic property of
a compound may be determined by in vivo or in vitro assays well
known in the art. For instance, the compound may be administered to
an animal and monitoring the insulin concentration over time.
Insulinotropic analogs of GLP-1(1-37) and exendin-4(1-39) refer to
the respective molecules wherein one or more of the amino acids
residues have been exchanged with other amino acid residues and/or
from which one or more amino acid residues have been deleted and/or
from which one or more amino acid residues have been added with the
proviso that said analogue either is insulinotropic or is a prodrug
of an insulinotropic compound. Examples of insulinotropic analogs
of GLP-1(1-37) are e.g. Met.sup.8-GLP-1(7-37) wherein the alanine
in position 8 has been replaced by methionine and the amino acid
residues in position 1 to 6 have been deleted, and
Arg.sup.34-GLP-1(7-37) wherein the valine in position 34 has been
replaced with arginine and the amino acid residues in position 1 to
6 have been deleted, and a fusion protein between GLP-1(7-37) and
human serum albumin. Examples of insulinotropic analogs of
exendin-4(1-39) is Ser.sup.2Asp.sup.3-exendin-4(1-39) wherein the
amino acid residues in position 2 and 3 have been replaced with
serine and aspartic acid, respectively (this particular analog also
being known in the art as exendin-3), and a fusion protein between
exendin-4(1-39) and human serum albumin. Insulinotropic derivatives
of GLP-1(1-37), exendin-4(1-39) and analogs thereof are what the
person skilled in the art considers to be derivatives of these
peptides, i.e. having at least one substituent which is not present
in the parent peptide molecule with the proviso that said
derivative either is insulinotropic or is a prodrug of an
insulinotropic compound. Examples of substituents are amides,
carbohydrates, alkyl groups and lipophilic substituents. Examples
of insulinotropic derivatives of GLP-1(1-37), exendin-4(1-39) and
analogs thereof are GLP-1(7-36)-amide, Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadecanoyl)))-GLP-
-1(7-37) and Tyr.sup.31-exendin-4(1-31)-amide. Further examples of
GLP-1(1-37), exendin-4(1-39), insulinotropic fragments thereof,
insulinotropic analogs thereof and insulinotropic derivatives
thereof are described in WO 98/08871, WO 99/43706, U.S. Pat. No.
5,424,286 and WO 00/09666.
[0054] The term "stable GLP-1 analog/derivative", as used herein
refers to a GLP-1(1-37) analog or derivative thereof which exhibits
an in vivo plasma elimination half-life of at least 10 hours in
man, as determined by the method described below. Examples of
stable derivatives of GLP-1 analogs can be found in WO 98/08871, WO
99/43706 and WO 02/46227. The method for determination of plasma
elimination half-life of a compound in man is : The compound is
dissolved in an isotonic buffer, pH 7.4, PBS or any other suitable
buffer. The dose is injected peripherally, preferably in the
abdominal or upper thigh. Blood samples for determination of active
compound are taken at frequent intervals, and for a sufficient
duration to cover the terminal elimination part (e.g. Pre-dose, 1,
2, 3, 4, 5, 6, 7, 8, 10, 12, 24 (day 2), 36 (day 2), 48 (day 3), 60
(day 3), 72 (day 4) and 84 (day 4) hours post dose). determination
of the concentration of active compound is performed as described
in Wilken et al., Diabetologia 43(51):A143, 2000. Derived
pharmacokinetic parameteres are calculated from the
concentration-time data for each individual subject by use of
non-compartmental methods, using the commercially available
software WinNonlin Version 2.1 (Pharsight, Cary, N.C., USA). The
terminal elimination rate constant is estimated by log-linear
regression on the terminal log-linear part of the
concentration-time curve, and used for calculating the elimination
half-life.
[0055] The term "stable exendin-4 analog/derivative", as used
herein refers to a exendin-4(1-39) analog or derivative thereof
which exhibits an in vivo plasma elimination half-life of at least
10 hours in man, as determined by the method described above.
Typical examples of stable exendin-4 analog/derivatives are
exendin-4 compounds chemically modified by acylation, PEGylation
and fused to serum albumin or fragments thereof.
[0056] The term "blood glucose regulator", as used herein refers to
any compound which is able to regulate the blood glucose level.
Examples of blood glucose regulators are insulin, insulin
derivatives, insulin analogues, compounds that stimulate signal
transduction mediated by an insulin receptor type tyrosine kinase
in a cell, certain protein-tyrosine phosphatases (PTP's), other
Type II antidiabetica, and other biologically active substances
having insulin releasing action.
[0057] The term "insulin", as used herein refers to insulin from
any species such as human insulin, porcine insulin, bovine insulin
and salts thereof such as zinc salts and protamin salts.
[0058] The term "insulin analogues", as used herein refers to
insulin wherein one or more of the amino acid residues have been
exchanged with another amino acid residue and/or from which one or
more amino acid residue has been deleted and/or from which one or
more amino acid residue has been added with the proviso that said
insulin analogue has a sufficient insulin activity to lower the
blood glucose level. Using results from the so-called free fat cell
assay, any skilled art worker, for example, a physician, knows when
and which dosages to administer of the insulin analogue. Examples
of insulin analogues are described in the following patents and
equivalents thereto: U.S. Pat. No. 5,618,913, EP 254,516, EP
280,534, U.S. Pat. Nos. 5,750,497, and 6,011,007. Examples of
specific insulin analogues are insulin aspart (i.e., Asp.sup.B28
human insulin), insulin lispro (i.e., Lys.sup.B28, Pro.sup.B29
human insulin), and insulin glargine (i.e., Gly.sup.A21,
Arg.sup.B31, Arg.sup.B32 human insulin).
[0059] The term "derivatives of insulin", as used herein are what a
skilled art worker generally considers derivatives, for example,
insulin having one or more substituents not present in the parent
insulin molecule. Also included in "derivatives of insulin" are
derivatives of insulin analogs. Examples of such compounds are
described in the following patents and equivalents thereto: U.S.
Pat. Nos. 5,750,497, and 6,011,007. An example of a derivative of
insulin is insulin detemir (i.e., des-Thr.sup.B30 human insulin
.gamma. Lys.sup.B29 tetradecanoyl).
[0060] The term "non-diabetic patient", as used herein refers to a
patient who has not been diagnosed as having diabetes.
[0061] In its broadest sense, the term a "critically ill patient"
(herein designated CIP), as used herein refers to a patient who has
sustained or are at risk of sustaining acutely life-threatening
single or multiple organ system failure due to disease or injury, a
patient who is being operated and where complications supervene,
and a patient who has been operated in a vital organ within the
last week or has been subject to major surgery within the last
week. In a more restricted sense, the term a "critically ill
patient", as used herein refers to a patient who has sustained or
are at risk of sustaining acutely life-threatening single or
multiple organ system failure due to disease or injury, or a
patient who is being operated and where complications supervene. In
an even more restricted sense, the term a "critically ill patient",
as used herein refers to a patient who has sustained or are at risk
of sustaining acutely life-threatening single or multiple organ
system failure due to disease or injury. Similarly, these
definitions apply to similar expressions such as "critical illness
in a patient" and a "patient is critically ill".
[0062] The term "Intensive Care Unit" (herein designated ICU), as
used herein refers to the part of a hospital where critically ill
patients are treated. Of course, this might vary from country to
country and even from hospital to hospital and said part of the
hospital may not necessary, officially, bear the name "Intensive
Care Unit" or a translation or derivation thereof. Of course, the
term "Intensive Care Unit" also covers a nursing home, a clinic,
for example, a private clinic, or the like if the same or similar
activities are performed there.
[0063] The term "Criticall illness polyneuropathy" (herein
designated CIPNP), as used herein refers to the specific type of
polyneuropathy that develops in patients treated within an ICU for
several days to weeks and this for a variety of primary injuries or
illnesses
[0064] The term "effective dosage", as used herein refers to a
dosage which is sufficient in order for the treatment of the
patient to be effective.
[0065] The term "administration of a GLP-1 compound in combination
with a second compound", as used herein refers to the
administration of the two compounds in overlapping time periods,
i.e. the patient is treated with the GLP-1 compound at a time where
said patient is also treated with the second compound or has been
treated with the second compound until 24 hours prior to the start
of administration of the GLP-1 compound. Hence "administration of a
GLP-1 compound in combination with a second compound" is taking
place unless the administration of the second compound is stopped
at least 24 hours before the start of administration of the GLP-1
compound, irrespective of whether the two compounds are
administered as separate pharmaceutical compositions.
[0066] The term "medicament", as used herein refers to a
pharmaceutical composition suitable for administration of the
pharmaceutically active compound to a patient.
[0067] The term "GLP-1 agonist", as used herein refers to a
molecule, preferably GLP-1 or an analogue or a derivative thereof,
or exendin or an analogue or a derivative thereof, or a
non-peptidyl compound, which interacts with the GLP-1 receptor and
induces the physiologyical and pharmacological characteristics of
the GLP-1 receptor. A GLP-1 agonist binds to the GLP-1 receptor
with an affinity constant K.sub.D, below 1 .mu.M, preferably below
100 nM. Methods for identifying GLP-1 agonists are described in WO
93/19175 (Novo Nordisk A/S). The term "GLP-1 agonist" is also
intended to comprise active metabolites and prodrugs thereof, such
as active metabolites and prodrugs of GLP-1 or an analogue or a
derivative thereof, or exendin or an analogue or a derivative
thereof, or a non-peptidyl compound. A "metabolite" is an active
derivative of a GLP-1 agonist produced when the GLP-1 agonist is
metabolized. A "prodrug" is a compound which is either metabolized
to a GLP-1 agonist or is metabolized to the same metabolite(s) as a
GLP-1 agonist.
DETAILED DESCRIPTION OF THE INVENTION
[0068] Usually the treatment of a critical ill patent requires
prolonged minute-to-minute therapy and/or observation, usually and
preferably in an intensive care unit (ICU) or a special hospital
unit, for example a post operative ward or the like, which is
capable of providing a high level of intensive therapy in terms of
quality and immediacy.
[0069] Examples of a critically ill patient is a patient in need of
cardiac surgery, cerebral surgery, thoracic surgery, abdominal
surgery, vascular surgery, or transplantation, or a patient
suffering from neurological diseases, cerebral trauma, respiratory
insufficiency, abdominal peritonitis, multiple trauma, severe
burns, or CIPNP.
[0070] The glucose metabolism of a clinical ill patient may be
controlled by clamping the blood glucose level within the ranges
mentioned in connection with the present invention. The skilled art
worker, for example, a physician, may do this using a GLP-1
compound. The skilled art worker is able to find the
pharmaceutically effective amount of the GLP-1 compound used and to
determine how often it is to be administered (depending on the
patients weight, gender, disease condition etc.).
[0071] Conveniently, the blood glucose level is kept within the
ranges mentioned in connection with the present invention for as
long a period of time as the patient is critically ill. Hence, as a
general rule, the blood glucose level is kept within the ranges
mentioned in connection with the present invention as long as the
patient is critically ill. Consequently, the blood glucose level is
usually kept within the ranges mentioned in connection with the
present invention for a period of time of more than about 8 hours,
preferably more than about 24 hours, even more preferred more than
about 2 days, especially more than about 4 days, and even more than
about 7 days. In certain cases, it may even be preferred that the
blood glucose level is kept within the ranges mentioned in
connection with the present invention after the patient
(previously) considered as being critically ill has been
transferred from the Intensive Care Unit to another part of the
hospital or even after said patient has left the hospital.
[0072] A critical ill patient, optionally entering an ICU, may be
fed continuously, on admission with mainly intravenous glucose (for
example, about 200 g to about 300 g per 24 hours) and from the next
day onward with a standardised feeding schedule aiming for a
caloric content up to between about 10 and about 40, preferably
between about 20 and about 30, non-protein Calories/kg/24 hours and
a balanced composition (for example, between about 0.05 and about
0.4, preferably between about 0.13 and about 0.26, g nitrogen/kg/24
hours and between about 20% and about 40% of non-protein Calories
as lipids) of either total parenteral, combined parenteral/enteral
or full enteral feeding, the latter mode attempted as early as
possible. Other concomitant ICU therapy can be left to the
discretion of attending physicians.
[0073] Alternatively, the following procedure can be used or it is
possible to use a combination or variant of these procedures, as
the physician considers advantageous for the patient: A critical
ill patient may be fed, on the admission day, using, for example, a
20% glucose infusion and from day 2 onward by using a standardised
feeding schedule consisting of normal caloric intake (for example,
about 25-35 Calories/kgBW/24 h) and balanced composition (for
example, about 20%-40% of the non-protein Calories as lipids and
about 1-2 g/kgBW/24 h protein) of either total parenteral, combined
parenteral/enteral or full enteral feeding, the route of
administration of feeding depending on assessment of feasibility of
early enteral feeding by the attending physician. All other
treatments, including feeding regimens, were according to standing
orders currently applied within the ICU.
[0074] In one embodiment the GLP-1 compound is GLP-1(7-37),
GLP-1(7-36) amide, or an analog thereof or a derivative thereof.
Such GLP-1 compounds include, but are not limited to,
Arg.sup.26-GLP-1(7-37); Arg.sup.34-GLP-1(7-37);
Lys.sup.36-GLP-1(7-37); Arg.sup.26,34Lys.sup.36-G- LP-1(7-37);
Arg.sup.26,34-GLP-1(7-37); Arg.sup.26,34Lys.sup.40-GLP-1(7-37)- ;
Arg.sup.26Lys.sup.36-GLP-1(7-37); Arg.sup.34Lys.sup.36-GLP-1(7-37)
Val.sup.8Arg.sup.22-GLP-1(7-37);
Met.sup.8Arg.sup.22-GLP-1(7-37);Gly.sup.- 8His.sup.22-GLP-1(7-37);
Val.sup.8His.sup.22-GLP-1(7-37); Met.sup.8His.sup.22-GLP-1(7-37);
His.sup.37-GLP-1(7-37); Gly.sup.8-GLP-1(7-37);
Val.sup.8-GLP-1(7-37); Met.sup.8-GLP-1(7-37);
Gly.sup.8Asp.sup.22-GLP-1(7-37); Val.sup.8Asp.sup.22-GLP-1(7-37);
Met.sup.8Asp.sup.22-GLP-1(7-37); Gly.sup.8Glu.sup.22-GLP-1(7-37);
Val.sup.8Glu.sup.22-GLP-1(7-37); Met.sup.8Glu.sup.22-GLP-1(7-37);
Gly.sup.8Lys.sup.22-GLP-1(7-37); Val.sup.8Lys.sup.22-GLP-1(7-37);
Met.sup.8Lys.sup.22-GLP-1(7-37); Gly.sup.8Arg.sup.22-GLP-1(7-37);
Val.sup.8Lys.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Glu.sup.22His.sup.37-- GLP-1(7-37);
Val.sup.8Glu.sup.22His.sup.37-GLP-1(7-37);
Met.sup.8Glu.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Lys.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8Lys.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Arg.sup.22His.sup.37-GLP-1(7-37);
Val.sup.8Arg.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8Arg.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8His.sup.22His.sup.37-GLP-1(7-37);
Val.sup.8His.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8His.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8His.sup.37-GLP-1(7-37); Val.sup.8His.sup.37-GLP-1(7-37);
Met.sup.8His.sup.37-GLP-1(7-37);
Gly.sup.8Asp.sup.22His.sup.37-GLP-1(7-37- );
Val.sup.8Asp.sup.22His.sup.37-GLP-1(7-37);
Met.sup.8Asp.sup.22His.sup.3- 7-GLP-1(7-37);
Arg.sup.26-GLP-1(7-36)-amide; Arg.sup.34-GLP-1(7-36)-amide;
Lys.sup.36-GLP-1(7-36)-amide;
Arg.sup.26,34Lys.sup.36-GLP-1(7-36)-amide;
Arg.sup.26,34-GLP-1(7-36)-amide;
Arg.sup.26,34Lys.sup.40-GLP-1(7-36)-amid- e;
Arg.sup.26Lys.sup.36-GLP-1(7-36)-amide:
Arg.sup.34Lys.sup.36-GLP-1(7-36- )-amide;
Gly.sup.8-GLP-1(7-36)-amide; Val.sup.8-GLP-1(7-36)-amide;
Met.sup.8-GLP-1(7-36)-amide; Gly.sup.8Asp.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Glu.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Asp.sup.22-GLP-- 1(7-36)-amide;
Met.sup.8Asp.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Glu.sup.22-GLP-1(7-36)-amide;
Val.sup.8Glu.sup.22-GLP-1(7-36)-am- ide;
Met.sup.8Glu.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Lys.sup.22-GLP-1(7-36- )-amide;
Val.sup.8Lys.sup.22-GLP-1(7-36)-amide; Met.sup.8Lys.sup.22-GLP-1(-
7-36)-amide; Gly.sup.8His.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Arg.sup.22-GLP-1(7-36)-amide;
Val.sup.8Arg.sup.22-GLP-1(7-36)-am- ide;
Met.sup.8Arg.sup.22-GLP-1(7-36)-amide;
Gly.sup.8His.sup.22-GLP-1(7-36- )-amide;
Val.sup.8His.sup.22-GLP-1(7-36)-amide; Met.sup.8His.sup.22-GLP-1(-
7-36)-amide; His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Arg.sup.22His.sup.37-G- LP-1(7-36)-amide;
Met.sup.8Arg.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8His.sup.37-GLP-1(7-36)-amide;
Val.sup.8His.sup.37-GLP-1(7-36)-am- ide;
Met.sup.8His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Asp.sup.22His.sup.37-- GLP-1(7-36)-amide;
Val.sup.8Asp.sup.22His.sup.37-1(7-36)-amide;
Met.sup.8Asp.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Glu.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8Glu.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Lys.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Lys.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8Lys.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Arg.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8His.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8His.sup.22His.sup.37-GLP-1(7-36)-amide; and derivatives
thereof.
[0075] In another embodiment the GLP-1 compound is a fusion protein
between GLP-1(7-37), an analogue or a derivative thereof, and human
serum albumin or a variant, e.g. fragment, thereof. In another
embodiment the GLP-1 compound is a fusion protein between
GLP-1(7-37), an analogue or a derivative thereof, and the Fc
portion of an immunoglobulin or a variant, e.g. fragment,
thereof.
[0076] GLP-1 analogues and derivatives which can be used according
to the present invention includes those referred to in WO 99/43705
(Novo Nordisk A/S), WO 99/43706 (Novo Nordisk A/S), WO 99/43707
(Novo Nordisk A/S), WO 98/08871 (Novo Nordisk A/S), WO 99/43708
(Novo Nordisk A/S), WO 99/43341 (Novo Nordisk A/S), WO 87/06941
(The General Hospital Corporation), WO 90/11296 (The General
Hospital Corporation), WO 91/11457 (Buckley et al.), WO 98/43658
(Eli Lilly & Co.), EP 0708179-A2 (Eli Lilly & Co.), EP
0699686-A2 (Eli Lilly & Co.), WO 01/98331 (Eli Lilly &
Co).
[0077] In another embodiment of the invention the GLP-1 compound is
selected from exendin as well as analogs, derivatives, and
fragments thereof, e.g. exendin-3 and exendin-4. Examples of
exendins as well as analogs, derivatives, and fragments thereof to
be included within the present invention are those disclosed in WO
9746584, U.S. Pat. No. 5,424,286 and WO 01/04156. U.S. Pat. No.
5,424,286 describes a method for stimulating insulin release with
an exendin polypeptide. The exendin polypeptides disclosed include
HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGX; wherein X=P or Y, and
HX1X2GTFITSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; wherein X1X2=SD
(exendin-3) or GE (exendin-4)). WO 9746584 describes truncated
versions of exendin peptide(s). The disclosed peptides increase
secretion and biosynthesis of insulin, but reduce those of
glucagon.
[0078] In another embodiment the GLP-1 compound is a fusion protein
between exendin-4(1-39), an analogue or a derivative thereof, and
human serum albumin or a variant, e.g. fragment, thereof. In
another embodiment the GLP-1 compound is a fusion protein between
exendin-4(1-39), an analogue or a derivative thereof, and the Fc
portion of an immunoglobulin or a variant, e.g. fragment, thereof.
WO 01/04156 describes exendin-4 analogs and derivatives as well as
the preparation of these molecules. Likewise, WO 02/46227 describes
GLP-1 compounds which are exendin-4 fusion proteins and the
preparation of these molecules.
[0079] GLP-1 compounds can be produced by appropriate
derivatization of an appropriate peptide backbone which has been
produced by recombinant DNA technology or by peptide synthesis
(e.g. Merrifield-type solid phase synthesis) as known in the art of
peptide synthesis and peptide chemistry.
[0080] The route of administration of GLP-1 compounds may be any
route, which effectively transports the active compound to the
appropriate or desired site of action, such as oral, nasal, buccal,
pulmonal, transdermal or parenteral.
[0081] Medicaments or pharmaceutical compositions containing a
GLP-1 compound, such as Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.s-
up..alpha.-hexadecanoyl)))-GLP-1(7-37), may be administered
parenterally to a critically ill patient and/or a CIPNP patient
and/or a potential CIPNP patient. Parenteral administration may be
performed by subcutaneous, intramuscular or intravenous injection
by means of a syringe, optionally a pen-like syringe.
Alternatively, parenteral administration can be performed by means
of an infusion pump. A further option is a composition which may be
a powder or a liquid for the administration of a GLP-1 compound in
the form of a nasal or pulmonal spray. As a still further option,
the GLP-1 compound can also be administered transdermally, e.g.
from a patch, optionally a iontophoretic patch, or transmucosally,
e.g. bucally. The above-mentioned possible ways to administer GLP-1
compounds are not considered as limiting the scope of the
invention.
[0082] Pharmaceutical compositions containing GLP-1 compounds, such
as Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadec-
anoyl)))-GLP-1(7-37), may be prepared by conventional techniques,
e.g. as described in Remington's Pharmaceutical Sciences, 1985 or
in Remington: The Science and Practice of Pharmacy, 19.sup.th
edition, 1995.
[0083] Thus, the injectable compositions of GLP-1 compounds can be
prepared using the conventional techniques of the pharmaceutical
industry which involves dissolving and mixing the ingredients as
appropriate to give the desired end product.
[0084] According to one procedure, e.g. Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadecanoyl)))-GLP-
-1(7-37) is dissolved in an amount of water which is somewhat less
than the final volume of the composition to be prepared. An
isotonicity agent, a preservative and a buffer are added as
required and the pH value of the solution is adjusted--if
necessary--using an acid, e.g. hydrochloric acid, or a base, e.g.
aqueous sodium hydroxide as needed. Finally, the volume of the
solution is adjusted with water to give the desired concentration
of the ingredients.
[0085] Examples of isotonic agents are sodium chloride, mannitol
and glycerol.
[0086] Examples of preservatives are phenol, m-cresol, methyl
p-hydroxybenzoate and benzyl alcohol.
[0087] Examples of suitable buffers are sodium acetate and sodium
phosphate.
[0088] Further to the above-mentioned components, solutions
containing a GLP-1 compound may also contain a surfactant in order
to improve the solubility and/or the stability of the peptide.
[0089] According to one embodiment of the present invention, the
GLP-1 compound is provided in the form of a composition suitable
for administration by injection. Such a composition can either be
an injectable solution ready for use or it can be an amount of a
solid composition, e.g. a lyophilised product, which has to be
dissolved in a solvent before it can be injected. The injectable
solution preferably contains not less than about 0.1 mg/ml,
typically from 0.1 mg/ml to 10 mg/ml, such as from 1 mg/ml to 5
mg/ml of GLP-1 compound.
[0090] GLP-1 compounds such as Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.ga-
mma.-Glu(N.sup..alpha.-hexadecanoyl)))-GLP-1(7-37) can be used in
the treatment of all critically ill patients and/or CIPNP patients
and/or potential CIPNP patients. The optimal dose level for any
patient (effective amount) will depend on the history and state of
that particular patient to be treated. The person skilled in the
art, e.g. a physician, will know how to determine the optimal dose
level in order to control the blood glucose level within intervals
mentioned herein.
[0091] Furthermore, the present GLP-1 compounds, preferably
Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadecanoyl)))-GLP-
-1(7-37), may be administered in combination with one or more
antihypertensive agents. Examples of antihypertensive agents are
.beta.-blockers such as alprenolol, atenolol, timolol, pindolol,
propranolol and metoprolol, ACE (angiotensin converting enzyme)
inhibitors such as benazepril, captopril, enalapril, fosinopril,
lisinopril, alatriopril, quinapril and ramipril, calcium channel
blockers such as nifedipine, felodipine, nicardipine, isradipine,
nimodipine, diltiazem and verapamil, and .alpha.-blockers such as
doxazosin, urapidil, prazosin and terazosin.
[0092] Also, the present GLP-1 compounds may be administered in
combination with a compound selected from human growth hormone,
growth hormone releasing compounds, a growth factor such as
prolactin or placental lactogen, FVII and other factors in the
blood clotting cascade.
[0093] The present invention also relates to a method of marketing
a GLP-1 compound, said method comprising the dissemination of
information about the indications, utilities and benefits of a
GLP-1 compound or a pharmaceutical composition comprising a GLP-1
compound, said indications, utilities, benefits and GLP-1 compounds
being according to the present invention. Another method of
marketing a GLP-1 compound according to the present invention is to
support a speaker disseminating information about the indications,
utilities and benefits of a GLP-1 compound or a pharmaceutical
composition comprising a GLP-1 compound, said indications,
utilities, benefits and GLP-1 compounds being according to the
present invention. Examples are supporting a speaker at a symposium
or congress within the fields of medicine, ICU and/or health care
economics.
[0094] The present invention also relates to advertising media to
disseminate information about the indications, utilities and
benefits of a GLP-1 compound or a pharmaceutical composition
comprising a GLP-1 compound, said indications, utilities, benefits
and GLP-1 compounds being according to the present invention.
Examples of advertising media and material and information media
and material is a brochure, pamphlet, or packaging material which
is used for the customer package such as the outer box, the inner
box, or a blister-pack, any printed material/leaflet supplied with
the medicament such as a package insert, a patient leaflet, or
patient information, a label, a web site, a movie, an advertising
movie, a video, a DVD, a CD-ROM and the like. The skilled art
worker knows how to manufacture the above advertising media and
material and information media and material. An example of a
brochure according to the present invention is a brochure in which
it is stated (or suggested) that insulin can be used to treat
critically ill patients and/or CIPNP patients, for example in an
ICU.
[0095] An advertising medium according to the present invention can
have the following text:
1 to physicians, especially those working in an Intensive Care
Unit: LIFE SAVING TREATMENT In order to save life, it is important
that the blood glucose level of a critically ill patient is kept
within the range from about 80 to about 110 mg/dL. This can be done
with no risk of hypoglycaemic event by using NN2211 from Novo
Nordisk A/S. More information will be available from
www.novonordisk.com.
[0096] The advertising media according to the present invention are
preferably presented or distrubuted to physicians working in an ICU
and persons responsible for the budget in an ICU.
[0097] According to one aspect, the present invention relates to a
use of a GLP-1 compound for the manufacture of a medicament for
treatment or cure of a critically ill patient and/or a CIPNP
patient and/or a potential CIPNP patient.
[0098] According to one embodiment, the present invention relates
to the novel uses described herein, wherein the treatment or cure
increases the survival rate of critically ill patients and/or CIPNP
patients and/or potential CIPNP patients.
[0099] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the treatment
or cure reduces the time where a critically ill patient and/or a
CIPNP patient and/or a potential CIPNP patient is hospitalized.
[0100] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
hospitalized in an ICU.
[0101] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for the manufacture of a medicament
for preventing that a patient becomes critically ill or develops
CIPNP.
[0102] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for the manufacture of a medicament
for prevention, treatment or cure of SIRS in a patient.
[0103] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for the manufacture of a medicament
for preventing or reducing the likelihood of a patient suffering
from bacteraemia, septicaemia and/or septic shock during
hospitalization.
[0104] According to one embodiment, the present invention relates
to the novel uses described herein, where the hospitalization is in
an ICU.
[0105] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
selected from a critically ill patient, a CIPNP patient, a
potential CIPNP patient, a SIRS patient and a potential SIRS
patient.
[0106] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for manufacturing a medicament for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potential CIPNP patient acquires an
infectious disease.
[0107] According to one embodiment, the present invention relates
to the novel uses described herein, wherein the infectious disease
has a mortal outcome.
[0108] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for manufacturing a medicament for
preventing or reducing the likelihood that a critically ill patient
and/or a CIPNP patient and/or a potential CIPNP patient dies due to
an infection.
[0109] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for manufacturing a medicament for
reducing the rate of infection with mortal outcome in critically
ill patients and/or CIPNP patients and/or potential CIPNP patients
in an ICU.
[0110] According to one embodiment, the present invention relates
to the novel uses described herein, wherein the treatment or cure
reduces mortality, duration of hospitalization, frequency of
bacteraemia, frequency of septicaemia, frequency of septic shock,
need for dialysis, and/or need for ventilatory support in said
patient.
[0111] According to a further aspect, the present invention relates
to a use of a GLP-1 compound for the manufacture of a medicament to
treat a critically ill patient and/or a CIPNP-patient and/or a
potential CIPNP-patient so that the patient is no longer in need of
vital organ system support or to treat a critically ill patient
and/or a CIPNP-patient and/or a potential CIPNP-patient so that it
is considered sufficient for the patient to receive at least about
two third of the caloric need through the normal enteral route to
reduce the risk or likelihood from multiple organ failure, to
reduce the risk or likelihood from multiple organ failure with a
proven septic focus on post-mortem examination, to reduce
mortality, for example, in-hospital mortality, to reduce the use of
mechanical ventilatory support, to reduce the likelihood of renal
replacement therapy and/or renal failure, to reduce the likelihood
of disturbed kidney function parameters, to reduce the likelihood
of hyperbilirubinemia, to reduce the likelihood for blood stream
infections, to reduce the likelihood of disturbance in markers of
inflammations and/or inflammatory responses, to reduce the use of
antibiotics, to reduce the amount of red cell transfusion, or to
reduce stress induced hyperglycaemia, or to reduce the likelihood
of the critically ill patient and/or the CIPNP-patient and/or the
potential CIPNP-patient having repetitive positive EMGs, or to
prevent or reduce the amount of ultimately futile intensive care to
a critically ill patient and/or a CIPNP-patient and/or a potential
CIPNP-patient, or to protect a critically ill patient and/or a
CIPNP-patient and/or a potential CIPNP-patient from cholestasis, or
to reduce the need for invasive treatment in a critically ill
patient and/or a CIPNP-patient and/or a potential
CIPNP-patient.
[0112] According to one embodiment, the present invention relates
to the novel uses described herein, wherein the GLP-1 compound is
GLP-1(7-36)-amide, GLP-1(7-37), or an analogue thereof or a
derivative thereof.
[0113] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is a derivative of GLP-1(7-36)-amide or GLP-1(7-37) which
comprises a lipophilic substituent.
[0114] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is Arg.sup.34,
Lys.sup.26(N.sup..epsilon.-(.gamma.-Glu(N.sup..alpha.-hexadec-
anoyl)))-GLP-1(7-37).
[0115] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is selected from the group consisting of
Gly.sup.8-GLP-1(7-36)-amide, Gly.sup.8-GLP-1(7-37),
Val.sup.8-GLP-1(7-36)-amide, Val.sup.8-GLP-1(7-37),
Val.sup.8Asp.sup.22-GLP-1(7-36)-amide,
Val.sup.8Asp.sup.22-GLP-1(7-37),
Val.sup.8Glu.sup.22-GLP-1(7-36)-amide;
Val.sup.8Glu.sup.22-GLP-1(7-37),
Val.sup.8Lys.sup.22-GLP-1(7-36)-amide,
Val.sup.8Lys.sup.22-GLP-1(7-37),
Val.sup.8Arg.sup.22-GLP-1(7-36)-amide,
Val.sup.8Arg.sup.22-GLP-1(7-37),
Val.sup.8His.sup.22-GLP-1(7-36)-amide,
Val.sup.8His.sup.22-GLP-1(7-37), analogues thereof and derivatives
thereof.
[0116] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is selected from the group consisting of
Arg.sup.26-GLP-1(7-37); Arg.sup.34-GLP-1(7-37);
Lys.sup.36-GLP-1(7-37); Arg.sup.26,34Lys.sup.36-G- LP-1(7-37);
Arg.sup.26,34-GLP-1(7-37); Arg.sup.26,34Lys.sup.40-GLP-1(7-37)- ;
Arg.sup.26Lys.sup.36-GLP-1(7-37); Arg.sup.34Lys.sup.36-GLP-1(7-37);
Val.sup.8Arg.sup.22-GLP-1(7-37); Met.sup.8Arg.sup.22-GLP-1(7-37);
Gly.sup.8His.sup.22-GLP-1(7-37); Val.sup.8His.sup.22-GLP-1(7-37);
Met.sup.8His.sup.22-GLP-1(7-37); His.sup.37-GLP-1(7-37);
Gly.sup.8-GLP-1(7-37); Val.sup.8-GLP-1(7-37);
Met.sup.8-GLP-1(7-37); Gly.sup.8Asp.sup.22-GLP-1(7-37);
Val.sup.8Asp.sup.22-GLP-1(7-37); Me.sup.8Asp.sup.22-GLP-1(7-37);
Gly.sup.8Glu.sup.22-GLP-1(7-37); Val.sup.8Glu.sup.22-GLP-1(7-37);
Met.sup.8Glu.sup.22-1(7-37); Gly.sup.8Lys.sup.22-GLP-1(7-37);
Val.sup.8Lys.sup.22-GLP-1(7-37); Met.sup.8Lys.sup.22-GLP-1(7-37);
Gly.sup.8Arg.sup.22-GLP-1(7-37);
Val.sup.8Lys.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Glu.sup.22His.sup.37-- GLP-1(7-37);
Val.sup.8Glu.sup.22His.sup.37-GLP-1(7-37);
Met.sup.8Glu.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Lys.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8Lys.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8Arg.sup.22His.sup.37-GLP-1(7-37);
Val.sup.8Arg.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8Arg.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8His.sup.22His.sup.37-GLP-1(7-37);
Val.sup.8His.sup.22His.sup.37-- GLP-1(7-37);
Met.sup.8His.sup.22His.sup.37-GLP-1(7-37);
Gly.sup.8His.sup.37-GLP-1(7-37); Val.sup.8His.sup.37-GLP-1(7-37);
Met.sup.8His.sup.37-GLP-1(7-37);
Gly.sup.8Asp.sup.22His.sup.37-GLP-1(7-37- );
Val.sup.8Asp.sup.22His.sup.37-GLP-1(7-37);
Met.sup.8Asp.sup.22His.sup.3- 7-GLP-1(7-37);
Arg.sup.26-GLP-1(7-36)-amide; Arg.sup.34-GLP-1(7-36)-amide;
Lys.sup.36-GLP-1(7-36)-amide;
Arg.sup.26,34Lys.sup.36-GLP-1(7-36)-amide;
Arg.sup.26,34-GLP-1(7-36)-amide;
Arg.sup.26,34Lys.sup.40-GLP-1(7-36)-amid- e;
Arg.sup.26Lys.sup.36-GLP-1(7-36)-amide;
Arg.sup.34Lys.sup.36-GLP-1(7-36- )-amide;
Gly.sup.8-GLP-1(7-36)-amide; Val.sup.8-GLP-1(7-36)-amide;
Met.sup.8-GLP-1(7-36)-amide; Gly.sup.8Asp.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Glu.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Asp.sup.22-GLP-- 1(7-36)-amide;
Met.sup.8Asp.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Glu.sup.22-GLP-1(7-36)-amide;
val.sup.8Glu.sup.22-GLP-1(7-36)-am- ide;
Met.sup.8Glu.sup.22-GLP-1(7-36)-amide;
Gly.sup.8Lys.sup.22-GLP-1(7-36- )-amide;
Val.sup.8Lys.sup.22-GLP-1(7-36)-amide; Met.sup.8Lys.sup.22-GLP-1(-
7-36)-amide; Gly.sup.8His.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Arg.sup.22-GLP-1(7-36)-amide;
Val.sup.8Arg.sup.22-GLP-1(7-36)-am- ide;
Met.sup.8Arg.sup.22-GLP-1(7-36)-amide;
Gly.sup.8His.sup.22-GLP-1(7-36- )-amide;
Val.sup.8His.sup.22-GLP-1(7-36)-amide; Met.sup.8His.sup.22-GLP-1(-
7-36)-amide; His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Arg.sup.22His.sup.37-G- LP-1(7-36)-amide;
Met.sup.8Arg.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8His.sup.37-GLP-1(7-36)-amide;
Val.sup.8His.sup.37-GLP-1(7-36)-am- ide;
Met.sup.8His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Asp.sup.22His.sup.37-- GLP-1(7-36)-amide;
Val.sup.8Asp.sup.22His.sup.37-GLP-1(7-36)-amide;
Met.sup.8Asp.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Glu.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8Glu.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Lys.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8Lys.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8Lys.sup.22His.sup.37-GLP-1(7-36)-amide;
Gly.sup.8Arg.sup.22His.sup.37-GLP-1(7-36)-amide;
Val.sup.8His.sup.22His.s- up.37-GLP-1(7-36)-amide;
Met.sup.8His.sup.22His.sup.37-GLP-1(7-36)-amide; and derivatives
thereof.
[0117] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is a stable GLP-1 analog/derivative.
[0118] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is exendin-4 or an analogue thereof or a derivative
thereof.
[0119] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is a stable exendin-4 analog/derivative.
[0120] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is to be administered parenterally.
[0121] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is administered by injection.
[0122] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is administered by infusion or drip.
[0123] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the dosage of
GLP-1 compound is from about 0.5 .mu.g/kg/day to about 20
.mu.g/kg/day.
[0124] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the dosage of
GLP-1 compound is from about 0.1 .mu.g/kg/day to about 2
.mu.g/kg/day.
[0125] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is used such that the blood glucose level is kept below an
upper limit which is about 110 mg/dL, about 120 mg/dL or about 130
mg/dL.
[0126] According to a further embodiment, the present invention
relates to the novel-uses described herein, wherein the GLP-1
compound is used such that the blood glucose level is kept within a
range where the lower limit is about 60 mg/dL, about 70 mg/dL or
about 80 mg/dL and the upper limit is about 110 mg/dL, about 120
mg/dL or about 130 mg/dL, preferably in the range of 80 to about
110 mg/dL.
[0127] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the GLP-1
compound is used such that the blood glucose level is kept within a
range from about 60 mg/dL to about 130 mg/dL, preferably from about
70 mg/dL to about 120 mg/dL, more preferred from about 80 mg/dL to
about 110 mg/dL.
[0128] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the blood
glucose level is kept within the specified range for a period of
more than about 8 hours, preferably for more than about 24 hours,
more preferred for more than about 2 days, even more preferred for
more than about 4 days, and even more preferred for more than about
7 days.
[0129] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein a second blood
glucose regulator is used.
[0130] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the second
blood glucose regulator is selected from insulin, insulin analogs,
insulin derivatives, insulin secretagogues, insulin compounds that
stimulate signal transduction mediated by an insulin receptor type
tyrosine kinase in a cell, protein-tyrosine phosphatases and Type
II antidiabetica.
[0131] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the second
blood glucose regulator is selected from insulin, an insulin
analog, an insulin derivative, a GLP-1 compound and an orally
administered blood glucose regulator.
[0132] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein treatment,
curing or prevention is performed by administering an effective
amount of the second blood glucose regulator.
[0133] According to a further aspect, the present invention relates
to administration of a GLP-1 compound in combination with one or
more antihypertensive agents for example .beta.-blockers such as
alprenolol, atenolol, timolol, pindolol, propranolol and
metoprolol, ACE (angiotensin converting enzyme) inhibitors such as
benazepril, captopril, enalapril, fosinopril, lisinopril,
alatriopril, quinapril and ramipril, calcium channel blockers such
as nifedipine, felodipine, nicardipine, isradipine, nimodipine,
diltiazem and verapamil, and a-blockers such as doxazosin,
urapidil, prazosin and terazosin.
[0134] According to a further aspect, the present invention relates
to administration of a GLP-1 compound in combination with a
compound selected from human growth hormone, growth hormone
releasing compounds, a growth factor such as prolactin or placental
lactogen, FVII and other factors in the blood clotting cascade.
[0135] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
a non-diabetic patient.
[0136] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
a human.
[0137] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
in need of cardiac surgery, cerebral surgery, thoracic surgery,
abdominal surgery, vascular surgery, or transplantation, or a
patient suffering from neurological diseases, cerebral trauma,
respiratory insufficiency, abdominal peritonitis, multiple trauma,
severe burns, or CIPNP.
[0138] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient is
fed parenterally.
[0139] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein the patient
receives at least about one third of the caloric need through the
normal enteral route, preferably at least about half of the caloric
need through the normal enteral route, most preferable at least
about two third of the caloric need through the normal enteric
route.
[0140] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein treatment,
curing or prevention is performed by administering an effective
amount of the GLP-1 compound.
[0141] According to a further aspect, the present invention relates
to the use of a GLP-1 compound for the treatment or cure of
critically ill patients and/or CIPNP patients and/or potential
CIPNP patients.
[0142] According to one embodiment, the present invention relates
to the novel uses described herein, wherein the treatment or cure
comprises a pharmaceutically effective composition comprising the
GLP-1 compound.
[0143] According to a further embodiment, the present invention
relates to the novel uses described herein, wherein said use is to
altain the clinical benefits mentioned in any one of the preceding
claims.
[0144] According to a further aspect, the present invention relates
to a kit of parts comprising
[0145] a medicament wherein is a GLP-1 compound and
[0146] an insert label stating the use of said medicament for
treating critically ill patients within an ICU.
[0147] According to a further aspect, the present invention relates
to a method of marketing a GLP-1 compound, said method comprising
the dissemination of information about the indications, utilities
and benefits of a GLP-1 compound or a pharmaceutical composition
comprising a GLP-1 compound, said indications, utilities, benefits
and GLP-1 compounds being described in the aspects, embodiments and
claims of the present invention.
[0148] According to one embodiment, the present invention relates
to the novel method described herein, wherein the information is
disseminated by means of printed material, oral presentation or
electromagnetic signals, such as via internet, telephone,
television, radio or computer.
[0149] According to a further embodiment, the present invention
relates to the novel methods described herein, wherein the
information is disseminated to physicians and/or persons
responsible for health care budgets, preferably to physicians
working in an ICU and persons responsible for an ICU budget.
[0150] According to a further aspect, the present invention relates
to an advertising medium to disseminate information about the
indications, utilities and benefits of a GLP-1 compound or a
pharmaceutical composition comprising a GLP-1 compound, said
indications, utilities, benefits and GLP-1 compounds being
described in the uses of the present invention.
[0151] According to one embodiment, the present invention relates
to the novel advertising media described herein, wherein said
advertising media are selected from the group consisting of a
brochure, pamphlet, prospectus, videotape, DVD disk and CD
disk.
DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENT
[0152] The terminology used herein is for the purpose of describing
particular embodiments only, and is not intended to limit the scope
of the present invention which will be limited only by the
appending claims. This invention is not limited to the particular
methodology, protocols, delivery forms and reagents described as
these may vary.
EXAMPLE 1
Materials and Methods
[0153] In a randomized, double-blind, placebo-controlled, crossover
study the effect of NN2211 on beta cell sensitivity to glucose was
tested in 10 subjects with type 2 diabetes following a single dose
of NN2211 (7.5 .mu.g/kg) or placebo. Using a graded glucose
infusion protocol with plasma glucose levels matched over the range
of 5 to 12 mmol/L beta cell sensitivity was assessed. Insulin
secretion rates (ISR) were estimated by deconvolution of
circulating C-peptide concentrations. Findings were compared to
responses of 10 healthy, nondiabetic volunteers to the same glucose
infusion protocol.
Results
[0154] Compared to placebo, a single dose of NN2211 increased
insulin and C-peptide levels, increased ISR area under the curve
(AUC) (1130.+-.150 vs. 668.+-.106 pmol/kg; p<0.001), and
increased slope of ISR vs. plasma glucose (1.26.+-.0.36 vs.
0.54.+-.0.18 pmol*L/(min*mmol*kg); p<0.014), to values similar
to nondiabetic controls who did not receive the drug (ISR AUC
1206.+-.99; slope of ISR vs. plasma glucose 1.44.+-.0.18). No
hypoglycemic events occurred. Importantly insulin secretion was
comparable to the non-diabetic controls at low glucose levels.
CONCLUSION
[0155] A single dose of the long-acting GLP-1 derivative, NN2211,
improves beta cell sensitivity to physiological hyperglycemia in
type 2 diabetes patients, and confirms that NN2211 provides a
glucose-dependent insulin secretion.
EXAMPLE 2
Material and Methods
[0156] In a prospective, 12 week, randomised, double-blind,
dose-response, placebo controlled and open label glimepiride study
in subjects with type 2 diabetes, the glucose lowering effect of
NN2211 was tested with the primary endpoint being the effect on
HbA1c after 12 weeks treatment (a recognised measure of overall
glycaemic control). Altogether 193 patients were equally randomised
to receive one of 5 dose levels of NN2211 (0.045, 0.225, 0.45,
0.60, or 0.75 mg), placebo (s.c. injection), or glimepiride (p.o.)
all given once daily. Placebo and NN2211 was double-blind, whereas
glimepiride was open-label. The dose of glimepiride was adjusted
during the first 4 weeks based on glycaemic control with a
treatment target of fasting serum glucose<7 mM, with a dose not
exceeding 4 mg/day.
Results
[0157] For the primary endpoint of the study HbA.sub.1c decreased
in all NNC 90-1170 treatment groups, except the one at the lowest
dosage. In comparison to the placebo group the decrease was
statistically significant for the two highest doses (0.60 and 0.75
mg). After 12 weeks treatment the mean decrease compared to placebo
in HbA.sub.1c was 0.70 and 0.75 percentage points in the 0.60 and
0.75 mg groups, respectively, (p=0.0002 and p<0.0001,
respectively.). Furthermore, mean serum fasting glucose decreased
by 2.14 and 1.82 mmol/L after 12 weeks in the 0.60 and 0.75 mg NNC
90-1170 dose groups, p<0.0001 and p=0.0003, respectively,
compared with placebo. The effect of glimepiride after 12 weeks
treatment a reduction compared to placebo of 0.74% (p=0.0001), and
-2.6 mM, on HbA1c and FSG, respectively. These effects were not
statistically different from the two highest doses of NN2211.
[0158] Furthermore, there were 7% of the subjects that reported any
hypoglycaemic episode in the two highest dose groups of NN2211, as
opposed to 31% in the glimepiride group.
Conclusion
[0159] This study demonstrates that NN2211 improves glyceamic
control in patients with type 2 diabetes, and furthermore, the low
incidence of any hypoglycaemic event also in comparison to
glimepiride (that acts by stimulating insulin secretion),
corroborates the glucose dependent insulin secretion of NN2211
described in example 1, and suggests its therapeutic advantage on
the side effect profile as compared to exogenous insulin
administration that is known to be associated with hypoglycaemia if
dosing is not carefully titrated. Furthermore, the once daily
dosing regimen of NN2211 would be a therapeutic advantage compared
to a carefully titrated insulin administration regimen.
EXAMPLE 3
[0160] Serves as an example of a study that could determine the
effect of NN2211 in critically ill patients in comparison to
intensive insulin treatment.
Methods
[0161] Study Population
[0162] All mechanically ventilated, adult (age>18 y)
patients.
[0163] Study Design and Treatment Protocols
[0164] At ICU admission, and following informed consent, patients
are randomized to either strict control of glycemia below 6.1
mmol/L (110 mg/dL) with continuously infused insulin, the
`intensive insulin schedule` (IIS), or using NN2211 given once
daily (1-5 mg).
[0165] Baseline Assessment and Data Collection
[0166] At baseline, demographic, diagnostic and therapeutic
information as well as information necessary to determine severity
of illness and utilization of ICU resources are obtained from each
patient . These include APACHE-II (Acute Physiology and Chronic
Health Evaluation) score with higher values indicating more severe
illness and simplified Therapeutic Intervention Scoring System
(TISS-28) with higher values indicating a higher number of
therapeutic interventions. APACHE II and TISS scores are calculated
daily from ICU admission to discharge or death.
[0167] Continuous blood samples for glucose, clinical chemistry,
hematology and markers of inflammation, blood culture (if
appropriate). Furthermore, electromyography (EMG) to screen for
Critical Illness Polyneuropathy, and in case of ICU death, a
post-mortem examination is performed to confirm the presumed cause
of death.
[0168] Endpoints
[0169] The primary endpoint would be death from all causes during
intensive care. Secondary outcome measures are in-hospital
mortality, incidence of prolonged intensive care dependency and
need for ICU re-admission, need for vital organ system support
comprising mechanical ventilatory support, renal replacement
therapy (continuous or intermittent hemofiltration or dialysis),
inotropic or vasopressor support, incidence of critical illness
polyneuropathy, the degree of inflammation, incidence of blood
stream infections and use of antibiotics, transfusion requirements
and incidence of hyperbilirubinemia. Furthermore, use of intensive
care resources should be analysed by cumulative TISS scores. In
order to accurately and objectively assess duration of ICU stay,
which is often influenced by non-patient related factors such as
bed availability on regular wards, patients are defined as
`dischargable from ICU` when they were no longer in need of vital
organ system support and received at least 2/3rd of the caloric
need through the normal enteral route or earlier when actually sent
to a ward.
[0170] By using published data on variability of the mortality
endpoint, together with an expectation of showing a similar effect
as intensive insulin therapy (non-inferiority) a sample size
calculation are performed in order to determine the number of
subjects needed to be recruited.
* * * * *
References