CA2260148C - Remedies for eating disorders - Google Patents
Remedies for eating disorders Download PDFInfo
- Publication number
- CA2260148C CA2260148C CA 2260148 CA2260148A CA2260148C CA 2260148 C CA2260148 C CA 2260148C CA 2260148 CA2260148 CA 2260148 CA 2260148 A CA2260148 A CA 2260148A CA 2260148 C CA2260148 C CA 2260148C
- Authority
- CA
- Canada
- Prior art keywords
- growth hormone
- hgh
- anorexia nervosa
- human growth
- treatment
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 208000030814 Eating disease Diseases 0.000 title abstract description 6
- 208000019454 Feeding and Eating disease Diseases 0.000 title abstract description 6
- 235000014632 disordered eating Nutrition 0.000 title abstract description 6
- 108010000521 Human Growth Hormone Proteins 0.000 claims abstract description 68
- 102000002265 Human Growth Hormone Human genes 0.000 claims abstract description 68
- 239000000854 Human Growth Hormone Substances 0.000 claims abstract description 68
- 208000000103 Anorexia Nervosa Diseases 0.000 claims abstract description 30
- 238000011282 treatment Methods 0.000 claims abstract description 29
- 230000020595 eating behavior Effects 0.000 claims abstract description 23
- 239000000095 Growth Hormone-Releasing Hormone Substances 0.000 claims abstract description 22
- 102000038461 Growth Hormone-Releasing Hormone Human genes 0.000 claims abstract description 22
- 101710142969 Somatoliberin Proteins 0.000 claims abstract description 22
- 230000002159 abnormal effect Effects 0.000 claims abstract description 20
- 239000003814 drug Substances 0.000 claims abstract description 11
- 229940124597 therapeutic agent Drugs 0.000 claims abstract description 10
- 102000004218 Insulin-Like Growth Factor I Human genes 0.000 claims description 21
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 claims description 21
- 210000004369 blood Anatomy 0.000 claims description 16
- 239000008280 blood Substances 0.000 claims description 16
- 102000018997 Growth Hormone Human genes 0.000 claims description 13
- 108010051696 Growth Hormone Proteins 0.000 claims description 13
- 239000000122 growth hormone Substances 0.000 claims description 13
- 230000004044 response Effects 0.000 claims description 10
- 230000005856 abnormality Effects 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 abstract description 16
- 208000028017 Psychotic disease Diseases 0.000 abstract description 14
- 238000009472 formulation Methods 0.000 abstract description 9
- 239000000203 mixture Substances 0.000 abstract description 9
- 235000016709 nutrition Nutrition 0.000 abstract description 7
- 230000035764 nutrition Effects 0.000 abstract description 7
- 235000005686 eating Nutrition 0.000 abstract description 6
- 230000028327 secretion Effects 0.000 abstract description 5
- 206010047700 Vomiting Diseases 0.000 abstract description 3
- 230000008673 vomiting Effects 0.000 abstract description 3
- 239000003204 tranquilizing agent Substances 0.000 abstract 1
- 230000002936 tranquilizing effect Effects 0.000 abstract 1
- 230000037396 body weight Effects 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 9
- 230000006872 improvement Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 229940063135 genotropin Drugs 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 201000000736 Amenorrhea Diseases 0.000 description 3
- 206010001928 Amenorrhoea Diseases 0.000 description 3
- 231100000540 amenorrhea Toxicity 0.000 description 3
- 230000001747 exhibiting effect Effects 0.000 description 3
- 230000002093 peripheral effect Effects 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 206010006895 Cachexia Diseases 0.000 description 2
- 206010013883 Dwarfism Diseases 0.000 description 2
- 206010020710 Hyperphagia Diseases 0.000 description 2
- 206010062767 Hypophysitis Diseases 0.000 description 2
- AUYYCJSJGJYCDS-LBPRGKRZSA-N Thyrolar Chemical compound IC1=CC(C[C@H](N)C(O)=O)=CC(I)=C1OC1=CC=C(O)C(I)=C1 AUYYCJSJGJYCDS-LBPRGKRZSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000026500 emaciation Diseases 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 210000003016 hypothalamus Anatomy 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 229960004502 levodopa Drugs 0.000 description 2
- 239000012931 lyophilized formulation Substances 0.000 description 2
- 208000003068 pituitary dwarfism Diseases 0.000 description 2
- 210000003635 pituitary gland Anatomy 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002269 spontaneous effect Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 208000016261 weight loss Diseases 0.000 description 2
- 230000004580 weight loss Effects 0.000 description 2
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 101100449518 Caenorhabditis elegans grh-1 gene Proteins 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 208000020401 Depressive disease Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 108010013127 Met-human growth hormone Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010052428 Wound Diseases 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 208000022531 anorexia Diseases 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 230000037237 body shape Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 206010061428 decreased appetite Diseases 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 206010016256 fatigue Diseases 0.000 description 1
- -1 glycirie Chemical class 0.000 description 1
- 230000035876 healing Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 230000000366 juvenile effect Effects 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 125000001360 methionine group Chemical group N[C@@H](CCSC)C(=O)* 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000004089 psychotropic agent Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000003127 radioimmunoassay Methods 0.000 description 1
- 201000000980 schizophrenia Diseases 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 210000001685 thyroid gland Anatomy 0.000 description 1
- 239000005495 thyroid hormone Substances 0.000 description 1
- 229940036555 thyroid hormone Drugs 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/27—Growth hormone [GH], i.e. somatotropin
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Endocrinology (AREA)
- Immunology (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
This invention relates to a therapeutic agent for the treatment of abnormal eating behavior. The psychotic symptoms characteristic of anorexia nervosa such as apocleisis, intentional vomiting, eating in secret and the like have been treated with tranquilizers and the like, but the effectiveness was only limited. By administration of a therapeutic agent according to the present invention, i.e., a human growth hormone (hGH) formulation, a will to eat can spontaneously be developed in a patient who previously received nutrition only passively by means of a forcible nutrition program or a nasal nutrition supply. It is effective especially against, the eating disorder anorexia nervosa, attributable possibly to an increased central growth hormone releasing factor (GRH)-hGH secretion system.
Description
Remedies for Eating Disorders Technical Fie1_d The present invention relates to a therapeutic agent for the treatment of a psychotic symptom accompanying anorexia nervosa. More particularly, the present invention relates to a therapeutic agent for the treatment of abnormal eating behavior in anorexia nervosa attributable to an abnormally increased central GRH level.
prior Art Anorexia nervosa (or nervous asitia, apocleisis) is a disease exhibiting psychotic symptoms such as characteristic desire for emaciation and abnormal eating behavior as well as somatic syrnpt.oms such as extreme leptosome observed as a we:ight loss of 20 % or more of the standard body weight as well as amenorrhea, and develops frequently in juvenile women. It is diagnosed generally based on the following clinical findings.
A: Abnormal weight loss of 20 % or more of standard body weight B: Abnormal eating behavior (apocleisis, vomiting, eating in secret, hyperphagia and the like) C: Obsessed recognition with regar_-ci to body weight or body shape D: Onset age of 30 years old or younger E: Amenorrhea (in women) F: Absence of organic disease causative of emaciation (such as schizophrenia and depression) It is a serious, sometimes fatal disease.
In current treatments, a less potent psychotropic agent or an antianxiety agent is administered depending on the symptoms and an oral tube feeding diet or a high calorie drip infusion is employed for recovery from extreme physical exhaustion (See, "Today's treatment guideline", IGAKUSHOIN (1995 Ed.), p248). However, no essential therapeutic agents capable of removing the psychotic symptoms characteristic of anorexia nervosa and also capable of normalizing the eating behavior have been reported.
On the other hand, human growth hormone (hereinafter abbreviated as hGH) is employed in the treatment of pituitary dwarfism and is believed to also be effective in the promotion of the healing of fractures and burn wounds and in the treatment of a patient with reduced absorption of nutrition. Nevertheless, except for the exaltation associated with recovery from a state of physical exhaustion, effectiveness of hGH against the typical psychot.ic symptoms has not been suggested.
Recently, WO 95/24919 disclosed that. administration of hGH is useful against various diseases caused by the reduction in triiodothyronine (T3) which is a thyroid hormone. The inventors mentioned anorexia nervosa as an example of a disease caused by T3 reduction syndrome, but all clinical effects of hGH they observed were an hGH-induced improvement in nutrition absorption in only the peripheral tissues after a trauma or an organ implantation, and all of their data (increased blood IGF-I
level and reduced urinary nitrogen) can be interpreted based on the known peripheral effects of hGH.
Summary of the Invention An object of the present invention is to provide a therapeutic agent for the treatment of the psychotic symptoms of anorexia nervosa, which may be a core of this disease. As a result:, a patient suffering from anorexia nervosa which is difficult to treat and which imposes a substantial load on the family and the physicians can satisfactorily be treated.
We focused on the findings that in anorexia nervosa the level of IGF-I (insulin-like growth factor-I) is low in spite of the state of exhaustion, exhibiting an increased blood hGH level. Extensive studies resulted in an understanding that, in this disease, the central GRH level is elevated and it triggers the psychotic symptoms. Then we administered hGH to a typical anorexia nervosa patient, and observed a psychotic symptom improving effect in addition to a peripheral nutriture recovering effect, thereby establishing the present invention.
These effects may be due to the negative feedback to the central GRH secretion by an exogeneous hGH.
Certain exemplary embodiments of the present invention provides a therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising a human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
Other exemplary embodiments provide for the use of a human growth hormone (hGH) in the manufacture of a therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
4a Another exemplary embodiment provides use of an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
Brief Description of the Drawinas Figure 1 shows an eating behavior surveillance table and a criteria for judgment made by the anorexia nervosa survey and study group of the Ministry of Health and Welfare.
prior Art Anorexia nervosa (or nervous asitia, apocleisis) is a disease exhibiting psychotic symptoms such as characteristic desire for emaciation and abnormal eating behavior as well as somatic syrnpt.oms such as extreme leptosome observed as a we:ight loss of 20 % or more of the standard body weight as well as amenorrhea, and develops frequently in juvenile women. It is diagnosed generally based on the following clinical findings.
A: Abnormal weight loss of 20 % or more of standard body weight B: Abnormal eating behavior (apocleisis, vomiting, eating in secret, hyperphagia and the like) C: Obsessed recognition with regar_-ci to body weight or body shape D: Onset age of 30 years old or younger E: Amenorrhea (in women) F: Absence of organic disease causative of emaciation (such as schizophrenia and depression) It is a serious, sometimes fatal disease.
In current treatments, a less potent psychotropic agent or an antianxiety agent is administered depending on the symptoms and an oral tube feeding diet or a high calorie drip infusion is employed for recovery from extreme physical exhaustion (See, "Today's treatment guideline", IGAKUSHOIN (1995 Ed.), p248). However, no essential therapeutic agents capable of removing the psychotic symptoms characteristic of anorexia nervosa and also capable of normalizing the eating behavior have been reported.
On the other hand, human growth hormone (hereinafter abbreviated as hGH) is employed in the treatment of pituitary dwarfism and is believed to also be effective in the promotion of the healing of fractures and burn wounds and in the treatment of a patient with reduced absorption of nutrition. Nevertheless, except for the exaltation associated with recovery from a state of physical exhaustion, effectiveness of hGH against the typical psychot.ic symptoms has not been suggested.
Recently, WO 95/24919 disclosed that. administration of hGH is useful against various diseases caused by the reduction in triiodothyronine (T3) which is a thyroid hormone. The inventors mentioned anorexia nervosa as an example of a disease caused by T3 reduction syndrome, but all clinical effects of hGH they observed were an hGH-induced improvement in nutrition absorption in only the peripheral tissues after a trauma or an organ implantation, and all of their data (increased blood IGF-I
level and reduced urinary nitrogen) can be interpreted based on the known peripheral effects of hGH.
Summary of the Invention An object of the present invention is to provide a therapeutic agent for the treatment of the psychotic symptoms of anorexia nervosa, which may be a core of this disease. As a result:, a patient suffering from anorexia nervosa which is difficult to treat and which imposes a substantial load on the family and the physicians can satisfactorily be treated.
We focused on the findings that in anorexia nervosa the level of IGF-I (insulin-like growth factor-I) is low in spite of the state of exhaustion, exhibiting an increased blood hGH level. Extensive studies resulted in an understanding that, in this disease, the central GRH level is elevated and it triggers the psychotic symptoms. Then we administered hGH to a typical anorexia nervosa patient, and observed a psychotic symptom improving effect in addition to a peripheral nutriture recovering effect, thereby establishing the present invention.
These effects may be due to the negative feedback to the central GRH secretion by an exogeneous hGH.
Certain exemplary embodiments of the present invention provides a therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising a human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
Other exemplary embodiments provide for the use of a human growth hormone (hGH) in the manufacture of a therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
4a Another exemplary embodiment provides use of an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
Brief Description of the Drawinas Figure 1 shows an eating behavior surveillance table and a criteria for judgment made by the anorexia nervosa survey and study group of the Ministry of Health and Welfare.
5 Figure 2 shows the change in the coridition in Case No.
1 before and after administration of hGH. The graph plotted with [x] shows the blood IGF-I levels, while the graph plotted with [0] shows the body weights.
Figure 3 shows the change in the condition in Case No.
1 before and after administration of hGH. The histogram shows the general improvement ratings of the psychotic symptoms of anorexia riervosa/abnormal, eating behavior based on the findings by a physician. The % values on the ordinate rep:resent the improvement ratings of the eating behavior, with 0`I representing an extremely abnormal eating behavior (score of 26 or h.igher in the table in Figure 1) and 100 representing a completely normal behavior.
Detailed Description of the Invention The present invention is described below.
Human growth hormone (hGH) has practically been used for about 20 years as a t::herapeuti.c agent for the treatment of pituitary dwarfism and various pharmaceutical formulations are marketed currently.
1 before and after administration of hGH. The graph plotted with [x] shows the blood IGF-I levels, while the graph plotted with [0] shows the body weights.
Figure 3 shows the change in the condition in Case No.
1 before and after administration of hGH. The histogram shows the general improvement ratings of the psychotic symptoms of anorexia riervosa/abnormal, eating behavior based on the findings by a physician. The % values on the ordinate rep:resent the improvement ratings of the eating behavior, with 0`I representing an extremely abnormal eating behavior (score of 26 or h.igher in the table in Figure 1) and 100 representing a completely normal behavior.
Detailed Description of the Invention The present invention is described below.
Human growth hormone (hGH) has practically been used for about 20 years as a t::herapeuti.c agent for the treatment of pituitary dwarfism and various pharmaceutical formulations are marketed currently.
In the present invention, any pharmaceutical formulation having an hGH activity may be employed. In view of the problems of the antigenicity, a mature hGH is preferred. Nevertheless, a purified product derived from a natural pituitary gland, Met-hGH having a methionine residue at the N-terminal, and a recombinant hGH variant may also be encompassed in the present invention as far as they are the pharmaceutical formulations having hGH
activities.
While the formulation may be a Liquid formulation or a lyophilized formulation, a subcutaneous formulation is particularly preferred. Each of these parenteral formulations may contain a stabilizer and a carrier known in the art, and is used preferably as an isotonic solution.
The carrier may be a plasma-derived protein such as albumin, an amino acid such as glycirie, a saccharide such as mannitol. Preferable examples are found in Japanese Patent Application Kohyo No. 503764/1991. Generally, a lyophilized formulation for subcutaneous or intramuscular administration is employed, and the representative TM
formulation is GENOTROPIN 16 IU (Pharmacia Upjohn) for injection.
In the present invention, the expression "psychotic symptoms accompanying ariorexia nervosa" means an abnormal concern or desire with regard to eating and resultant abnormal eating behavior (apocleisis, vomiting, eating in secret, hyperphagia). While concrete criteria employed in the diagnosis may vary depending on the findings by medical specialists, a standard is shown in F'igure 1 which shows an eating behavior surveillance table and a criteria for judgment made by Lhe specified diseases/anorexia nervosa survey and study group of the Ministry of Health and Welfare.
In the present invention, the expression "abnormal biochemical parameters" means that the level of an endogeneous hormone or a neurotransmitter is significantly different from a standard level in healthy humans or from the level observed in an patient when the identical patient was in a normal condition.
The expression "a high central growth hormone release factor (GRH) level" means a hypersecretion of GRH or hGH in the central nerve/hypothalamus or in the pituitary gland, which is identified usually by a plasma GRH level determined by a radioimmunoassay or an enzyme immunoassay not less than 30 pg/ml which is the upper limit of the normal range (3 to 30 pg/m1) [Clin. Chim. Acta; Vol. 202, p243-254 (1991) and C.lin. Chem. Enzym. Communs.; Vol. 4, p305-310 (1992)]. An indirect assumption may be made based on an hGH level in peripheral blood not less than 10 ng/ml in the absence of organic causative diseases such as hGH-producing tumor.
activities.
While the formulation may be a Liquid formulation or a lyophilized formulation, a subcutaneous formulation is particularly preferred. Each of these parenteral formulations may contain a stabilizer and a carrier known in the art, and is used preferably as an isotonic solution.
The carrier may be a plasma-derived protein such as albumin, an amino acid such as glycirie, a saccharide such as mannitol. Preferable examples are found in Japanese Patent Application Kohyo No. 503764/1991. Generally, a lyophilized formulation for subcutaneous or intramuscular administration is employed, and the representative TM
formulation is GENOTROPIN 16 IU (Pharmacia Upjohn) for injection.
In the present invention, the expression "psychotic symptoms accompanying ariorexia nervosa" means an abnormal concern or desire with regard to eating and resultant abnormal eating behavior (apocleisis, vomiting, eating in secret, hyperphagia). While concrete criteria employed in the diagnosis may vary depending on the findings by medical specialists, a standard is shown in F'igure 1 which shows an eating behavior surveillance table and a criteria for judgment made by Lhe specified diseases/anorexia nervosa survey and study group of the Ministry of Health and Welfare.
In the present invention, the expression "abnormal biochemical parameters" means that the level of an endogeneous hormone or a neurotransmitter is significantly different from a standard level in healthy humans or from the level observed in an patient when the identical patient was in a normal condition.
The expression "a high central growth hormone release factor (GRH) level" means a hypersecretion of GRH or hGH in the central nerve/hypothalamus or in the pituitary gland, which is identified usually by a plasma GRH level determined by a radioimmunoassay or an enzyme immunoassay not less than 30 pg/ml which is the upper limit of the normal range (3 to 30 pg/m1) [Clin. Chim. Acta; Vol. 202, p243-254 (1991) and C.lin. Chem. Enzym. Communs.; Vol. 4, p305-310 (1992)]. An indirect assumption may be made based on an hGH level in peripheral blood not less than 10 ng/ml in the absence of organic causative diseases such as hGH-producing tumor.
The expression "a reduced blood IGF-I response to an increased growth hornione (hGH)" means a condition in which the blood IGF-I level is not elevated in spite of higher blood hGH level, i.e., not less than 10 ng/ml which is the upper limit of the normal range. Typically, a condition in which the blood IGF-I level is 200 ng/ml or less and 20 times below the blood hGH level is applicable.
Since, in such coridition, no negative feedback by IGF-I occurs, the GRH producti_on in the hypothalamus is increased abnormally, resulting in an abnormality in the appetite center, which may lead to the abnormal eating behavior.
While hGH may be administered subcutaneously, intravenously or intramuscularly, it is usually administered subcutaneously. The dose and the frequency of the administration of hGH may vary depending on the condition, age and sex of a patient, etc. and one session generally comprises 0.05 to 5 units/day for 3 months, preferably 0.2 to 1 unit,/day for 1 week or longer.
As described above, an hGH-containing formulation according to the present invention is capable of improving psychotic svmptoms, particularly the abnormal eating behavior based on the central abnormality, in a patient having anorexia nervosa. It enables a novel therapy in a clinical practice currently having no particularly effective pharmaceuticals.
Examples The present invention is further described in the following examples.
Examu1Ze 1 Case No. 1 Pretreatment findinas The patient was a 17 year old woman diagnosed with anorexia nervosa accompanied with major symptoms such as weight loss, fatigue and amenorrhea. The body weight and the stature at the initiation of the treatment were 37.8 kg and 156.0 cm (BMI:15.5).
The biochemical parameters of endocrinal function were as foilows.
[Thyroid functions] T3: Low level (78.5 ng/dl), T4: Low level (6.8 g/dl), TBG: Low level (18.1 g/ml), TRH test:
Retarded response, Blood TSH levels (1.9, 13.5, 20.7, 24.5 and 27.5 IU/ml) after TRH loadirig (0, 30, 60, 90 and 120 minutes).
[Growth hormone secretion functi.ons] GRH test: Normal response, 1-DOPA test: Low response (See Table 1).
Table 1 GH secretion (ng/ml) Time after loading GRH 1.-DOPA
0 15.2 2.9 69.2 -30 51.6 2.9 60 40.5 6.1 90 1.4.9 2.2 120 minutes 2.8 3.6 [IGF-I secretion function] IGF-1: 40.4 (GH: 5.9 ng/ml), IGF-I:39.8 (GH: 5.9 ng/ml). 'I'he blood samples taken 5 twice exhibited an IGF-I level. which was particularly low relative to the GH level.
Case No. 1. Treatment As shown in Figure 2, a forcible nutrition program for about 50 days after admission (December, 1995) resulted in 10 no satisfactory weight gain or improvement in eating behavior. Accordingly, for the purpose of recovering physical strength, a nasal nutrition supply was initiated at the 30th day, and after 20 days no spontaneous eating was observed and no improvement in the psychotic symptoms 15 were observed., although the body weight and the IGF-I level were increased slightly. Administration of 0.5 IU/day of a recombinant hGH formulation (GENOTROPIN for injection (Pharmacia/Upjohn)) initiated on the 40th day resulted in a rapid weight gain and an increase in the IGF-I level as well as spontaneous eating whicti. began 2 days after initiation of the administration, exhibiting a marked improvement in the eating behavior. On the 30th day of the hGH treatment, the body weight was 45.() kg and the IGF-I
level was 300 ng/ml, indicating the recovery of the normal levels. The psychotic symptoms/eating disorder was considered to be removed, and she now receives continuous hGH treatment (May, 1996) and shows no psychotic symptoms of anorexia nervosa or eating disorder. Figure 2 and Figure 3 show the conditions before and after hGH treatment.
After 1 year of the growth hormone treatment, the patient showed the score of 8 in total for the 26 questions in the eatinq behavior surveillance table shown Figure 1 (a score of 20 or higher is required for the abnormal eating behavior in this criteria). In view of the score before the growth hormone treatment which was 26 as well as a typical image of anorexia nervosa observed previously, the growth hormone treatment is considered to be extremely useful for improving the psychotic symptoms and eating disorder associated with anorexia nervosa.
Example 2 Case No. 2. Treatment The patient was an 18 year old woman (body weight:
36.6 kg, stature: 160 cm). The total score was 23 before the growth hormone treatment, but reduced to 16 after the treatment with 1 IU of a recombinant hGH formulation (GENOTROPIN for injection (Pharmacia/Upjohn) ) once a day continuously for 2 weeks.
Example 3 Case No. 3, Treatment The patient was a 23 year old woman (body weight: 32 kg, stature: 154 cm) The abnormal eating behavior score was 30 before the growth hormone treatment, but reduced to 25 after the treatment with 1 IU of a recombinant hGH
formulation (GENOTROPIN for injection (Pharmacia/Upjohn)) once a day continuously for 2 weeks.
Since, in such coridition, no negative feedback by IGF-I occurs, the GRH producti_on in the hypothalamus is increased abnormally, resulting in an abnormality in the appetite center, which may lead to the abnormal eating behavior.
While hGH may be administered subcutaneously, intravenously or intramuscularly, it is usually administered subcutaneously. The dose and the frequency of the administration of hGH may vary depending on the condition, age and sex of a patient, etc. and one session generally comprises 0.05 to 5 units/day for 3 months, preferably 0.2 to 1 unit,/day for 1 week or longer.
As described above, an hGH-containing formulation according to the present invention is capable of improving psychotic svmptoms, particularly the abnormal eating behavior based on the central abnormality, in a patient having anorexia nervosa. It enables a novel therapy in a clinical practice currently having no particularly effective pharmaceuticals.
Examples The present invention is further described in the following examples.
Examu1Ze 1 Case No. 1 Pretreatment findinas The patient was a 17 year old woman diagnosed with anorexia nervosa accompanied with major symptoms such as weight loss, fatigue and amenorrhea. The body weight and the stature at the initiation of the treatment were 37.8 kg and 156.0 cm (BMI:15.5).
The biochemical parameters of endocrinal function were as foilows.
[Thyroid functions] T3: Low level (78.5 ng/dl), T4: Low level (6.8 g/dl), TBG: Low level (18.1 g/ml), TRH test:
Retarded response, Blood TSH levels (1.9, 13.5, 20.7, 24.5 and 27.5 IU/ml) after TRH loadirig (0, 30, 60, 90 and 120 minutes).
[Growth hormone secretion functi.ons] GRH test: Normal response, 1-DOPA test: Low response (See Table 1).
Table 1 GH secretion (ng/ml) Time after loading GRH 1.-DOPA
0 15.2 2.9 69.2 -30 51.6 2.9 60 40.5 6.1 90 1.4.9 2.2 120 minutes 2.8 3.6 [IGF-I secretion function] IGF-1: 40.4 (GH: 5.9 ng/ml), IGF-I:39.8 (GH: 5.9 ng/ml). 'I'he blood samples taken 5 twice exhibited an IGF-I level. which was particularly low relative to the GH level.
Case No. 1. Treatment As shown in Figure 2, a forcible nutrition program for about 50 days after admission (December, 1995) resulted in 10 no satisfactory weight gain or improvement in eating behavior. Accordingly, for the purpose of recovering physical strength, a nasal nutrition supply was initiated at the 30th day, and after 20 days no spontaneous eating was observed and no improvement in the psychotic symptoms 15 were observed., although the body weight and the IGF-I level were increased slightly. Administration of 0.5 IU/day of a recombinant hGH formulation (GENOTROPIN for injection (Pharmacia/Upjohn)) initiated on the 40th day resulted in a rapid weight gain and an increase in the IGF-I level as well as spontaneous eating whicti. began 2 days after initiation of the administration, exhibiting a marked improvement in the eating behavior. On the 30th day of the hGH treatment, the body weight was 45.() kg and the IGF-I
level was 300 ng/ml, indicating the recovery of the normal levels. The psychotic symptoms/eating disorder was considered to be removed, and she now receives continuous hGH treatment (May, 1996) and shows no psychotic symptoms of anorexia nervosa or eating disorder. Figure 2 and Figure 3 show the conditions before and after hGH treatment.
After 1 year of the growth hormone treatment, the patient showed the score of 8 in total for the 26 questions in the eatinq behavior surveillance table shown Figure 1 (a score of 20 or higher is required for the abnormal eating behavior in this criteria). In view of the score before the growth hormone treatment which was 26 as well as a typical image of anorexia nervosa observed previously, the growth hormone treatment is considered to be extremely useful for improving the psychotic symptoms and eating disorder associated with anorexia nervosa.
Example 2 Case No. 2. Treatment The patient was an 18 year old woman (body weight:
36.6 kg, stature: 160 cm). The total score was 23 before the growth hormone treatment, but reduced to 16 after the treatment with 1 IU of a recombinant hGH formulation (GENOTROPIN for injection (Pharmacia/Upjohn) ) once a day continuously for 2 weeks.
Example 3 Case No. 3, Treatment The patient was a 23 year old woman (body weight: 32 kg, stature: 154 cm) The abnormal eating behavior score was 30 before the growth hormone treatment, but reduced to 25 after the treatment with 1 IU of a recombinant hGH
formulation (GENOTROPIN for injection (Pharmacia/Upjohn)) once a day continuously for 2 weeks.
Claims (8)
1. A therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising a human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
2. Use of a human growth hormone (hGH) in the manufacture of a therapeutic agent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa comprising an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent, wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
3. Use of an effective amount of human growth hormone (hGH) in admixture with a pharmaceutically acceptable carrier or diluent for the treatment of a human patient suffering from abnormal eating behavior accompanied with anorexia nervosa wherein the anorexia nervosa is accompanied by abnormality in biochemical parameters of increased level of central growth hormone releasing factor (GRH) or reduced blood IGF-I response to increased growth hormone (hGH).
4. The use according to Claim 2 or 3, wherein the human growth hormone is in a form for administration intravenously.
5. The use according to Claim 2 or 3, wherein the human growth hormone is in a form for administration intramuscularly.
6. The use according to Claim 2 or 3, wherein the human growth hormone is in a form for administration subcutaneously.
7. The use according to Claim 2 or 3, wherein the human growth hormone is in a form for administration comprising 0.05 to 5 units/day of human growth hormone for three months.
8. The use according to Claim 2 or 3, wherein the human growth hormone is in a form for administration comprising 0.2 to 1 units/day of human growth hormone for at least one week.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP20124896 | 1996-07-10 | ||
| JP8/201248 | 1996-07-10 | ||
| PCT/JP1997/002283 WO1998001152A1 (en) | 1996-07-10 | 1997-07-02 | Remedies for eating disturbance |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2260148A1 CA2260148A1 (en) | 1998-01-15 |
| CA2260148C true CA2260148C (en) | 2010-03-30 |
Family
ID=42062551
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2260148 Expired - Fee Related CA2260148C (en) | 1996-07-10 | 1997-07-02 | Remedies for eating disorders |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2260148C (en) |
-
1997
- 1997-07-02 CA CA 2260148 patent/CA2260148C/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| CA2260148A1 (en) | 1998-01-15 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Clemmons et al. | Reversal of diet-induced catabolism by infusion of recombinant insulin-like growth factor-I in humans | |
| Rosenfeld et al. | Both human pituitary growth hormone and recombinant DNA-derived human growth hormone cause insulin resistance at a postreceptor site | |
| EP0309100B1 (en) | Use of amylin or CGRP for the treatment of diabetes mellitus | |
| EP0631505B2 (en) | Use of a peptide | |
| AU624595B2 (en) | Method for treating and preventing secondary effects of hyperinsulinemia and for treating type 2 diabetes, obesity and hyperlipidemia by application of insulin-like growth factor (IGF I) | |
| AU642665B2 (en) | Treatment of insulin-resistant diabetes | |
| US6174857B1 (en) | Composition and method for the treatment of osteoporosis in mammals | |
| US7291594B2 (en) | GLP-1 derivative and preparation thereof absorbable via mucous membrane | |
| US7910548B2 (en) | Methods for treating obesity | |
| WO1996040220A1 (en) | Treatment of type ii diabetes mellitus with amylin agonists | |
| AU669894B2 (en) | Use of IGF-1 | |
| US20120196799A1 (en) | Amylin Family Peptides and Methods for Making and Using Them | |
| JPH08500827A (en) | Method of systemic treatment of catabolism and systemic tissue wounds | |
| US8168233B2 (en) | Treatment of pancreatitis with amylin | |
| CA2260148C (en) | Remedies for eating disorders | |
| EP0916345B1 (en) | Human growth hormone for treating anorexia nervosa | |
| EP1229927B1 (en) | Use of a growth hormone or a growth hormone secretagogue for appetite-suppression or induction of satiety | |
| CA2237643C (en) | Therapeutic agent for acute hepatic failure | |
| JPH06510753A (en) | Compositions containing insulin and amylin for treating insulin-deficient mammals | |
| JPWO1998001152A1 (en) | Eating disorder treatment | |
| Tanaka | Therapeutic criteria and evaluation of clinical response in growth hormone deficient children in Japan | |
| JP2003526675A (en) | Use of growth hormone at low doses | |
| JPWO2000009147A1 (en) | Blood sugar regulators |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKLA | Lapsed |
Effective date: 20160704 |