MXPA97009234A - Preparation for the diagnosis of the metabolic syndrome and diseases that include the sindr - Google Patents
Preparation for the diagnosis of the metabolic syndrome and diseases that include the sindrInfo
- Publication number
- MXPA97009234A MXPA97009234A MXPA/A/1997/009234A MX9709234A MXPA97009234A MX PA97009234 A MXPA97009234 A MX PA97009234A MX 9709234 A MX9709234 A MX 9709234A MX PA97009234 A MXPA97009234 A MX PA97009234A
- Authority
- MX
- Mexico
- Prior art keywords
- cortisol
- novel use
- dexamethasone
- metabolic syndrome
- content
- Prior art date
Links
- 208000001145 Metabolic Syndrome Diseases 0.000 title claims abstract description 14
- 238000003745 diagnosis Methods 0.000 title claims abstract description 5
- 208000008466 Metabolic Disease Diseases 0.000 title description 2
- JYGXADMDTFJGBT-VWUMJDOOSA-N Cortisol Chemical compound O=C1CC[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 JYGXADMDTFJGBT-VWUMJDOOSA-N 0.000 claims abstract description 56
- 229960000890 hydrocortisone Drugs 0.000 claims abstract description 56
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 20
- 210000001015 Abdomen Anatomy 0.000 claims abstract description 14
- 239000000556 agonist Substances 0.000 claims abstract description 14
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 206010012601 Diabetes mellitus Diseases 0.000 claims abstract description 7
- 206010022489 Insulin resistance Diseases 0.000 claims abstract description 5
- 210000004369 Blood Anatomy 0.000 claims abstract description 4
- 206010020772 Hypertension Diseases 0.000 claims abstract description 4
- 239000008280 blood Substances 0.000 claims abstract description 4
- 229960003957 Dexamethasone Drugs 0.000 claims description 20
- UREBDLICKHMUKA-CXSFZGCWSA-N Dexamethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(F)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O UREBDLICKHMUKA-CXSFZGCWSA-N 0.000 claims description 20
- 210000002966 Serum Anatomy 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 7
- 210000003296 Saliva Anatomy 0.000 claims description 5
- 150000001886 cortisols Chemical class 0.000 claims description 3
- 239000003862 glucocorticoid Substances 0.000 claims description 2
- 239000002395 mineralocorticoid Substances 0.000 claims description 2
- 230000001270 agonistic Effects 0.000 claims 1
- 208000008589 Obesity Diseases 0.000 abstract description 11
- 235000020824 obesity Nutrition 0.000 abstract description 11
- 239000003925 fat Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 210000000683 Abdominal Cavity Anatomy 0.000 description 3
- 230000028327 secretion Effects 0.000 description 3
- 239000000055 Corticotropin-Releasing Hormone Substances 0.000 description 2
- 229940088597 Hormone Drugs 0.000 description 2
- 206010033307 Overweight Diseases 0.000 description 2
- 230000003042 antagnostic Effects 0.000 description 2
- 239000005557 antagonist Substances 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 238000009114 investigational therapy Methods 0.000 description 2
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- 239000011707 mineral Substances 0.000 description 2
- 235000020825 overweight Nutrition 0.000 description 2
- 229940035620 ACTH and synthetic analog preparations Drugs 0.000 description 1
- 210000000577 Adipose Tissue Anatomy 0.000 description 1
- 210000004556 Brain Anatomy 0.000 description 1
- 229940065521 Glucocorticoid inhalants for obstructive airway disease Drugs 0.000 description 1
- 210000001624 Hip Anatomy 0.000 description 1
- 210000003016 Hypothalamus Anatomy 0.000 description 1
- 102000004877 Insulin Human genes 0.000 description 1
- 108090001061 Insulin Proteins 0.000 description 1
- 206010057840 Major depression Diseases 0.000 description 1
- 230000036740 Metabolism Effects 0.000 description 1
- 210000003635 Pituitary Gland Anatomy 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- 229940037128 Systemic Glucocorticoids Drugs 0.000 description 1
- 208000001072 Type 2 Diabetes Mellitus Diseases 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001684 chronic Effects 0.000 description 1
- 201000000522 chronic kidney disease Diseases 0.000 description 1
- IDLFZVILOHSSID-OVLDLUHVSA-N corticotropin Chemical compound C([C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)NC(=O)[C@@H](N)CO)C1=CC=C(O)C=C1 IDLFZVILOHSSID-OVLDLUHVSA-N 0.000 description 1
- 230000001419 dependent Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 230000003828 downregulation Effects 0.000 description 1
- 201000003104 endogenous depression Diseases 0.000 description 1
- 239000003688 hormone derivative Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 230000003340 mental Effects 0.000 description 1
- 230000002503 metabolic Effects 0.000 description 1
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- 239000002438 stress hormone Substances 0.000 description 1
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Abstract
The present invention relates to the use of cortisol agonist to prepare a system for the diagnosis of the metabolic syndrome and related conditions such as belly obesity, insulin resistance including the increased risk of developing senile diabetes, i.e. type II diabetes, a high content of fat in the blood and a high blood pressure, in which system, the dose of the cortisol agonist is in a range where a difference is obtained in the inhibitory effect of the self-production of cortisol in individuals suffering from metabolic syndrome , compared to normal values
Description
PREPARATION FOR THE DIAGNOSIS OF METABOLIC SYNDROME AND DISEASES THAT INCLUDE THE
SYNDROME
DESCRIPTION OF THE INVENTION
BACKGROUND
Metabolic syndrome is characterized by an increased amount of adipose tissue within the abdominal cavity (popularly called belly obesity), insulin resistance with increased risk of developing senile diabetes, ie, type II diabetes (= NIDDM, diabetes non-insulin-dependent mellitus), high levels of fats in the blood and high blood pressure. Parallel to this is the increased risk of coronary conditions, stroke, sudden death and other arteriosclerotic conditions. A hypothetical explanation for the metabolic syndrome may be an overproduction of cortisol, a stress hormone, which causes the accumulation of fat within the abdominal cavity and insulin resistance. Theoretically, this can, through metabolic side effects, explain the other disorders related to the metabolic syndrome. In Metabolism, vol. 41, No. 8, 1992, pages 882-886, it is shown that women with an obese belly have a higher cortisol secretion than "uniformly obese" women. The same paper describes the effects of acute mental stress on the production of cortisol. It has been shown that women with an obese belly, at a given tension signal, produced more cortisol than women of "uniform obesity". This suggested, but did not prove, that there may be a relationship between belly tension and obesity. A dexamethasone inhibitor test was performed with 1 mg of dexamethasone and the subsequent measurement of the cortisol content in the serum. No difference in the inhibitory effect on cortisol production was found between the groups of women with obese abdomen and women uniformly obese and normal values. Cortisol analogues, for example dexamethasone, have been used for many years to trace the so-called endogenous depressions (usually hereditary) in humans. However, the mechanism behind the test is still unknown.
OBJ ETO OF THE I NVENTION AND CHARACTERI STI CAS MAS I M PO RTANTES
The object of the present invention is to find a diagnostic test by which individuals, who are at risk of being affected by one or more of the symptoms and / or conditions characteristic of the metabolic syndrome described above, can be identified at an early stage . In the present invention, this is achieved by a diagnostic system, which as an active substance has cortisol agonists of a dose in a range where a difference in the inhibitory effect of autonomous cortisol production between individuals with the metabolic syndrome or one or more of the related risks / conditions and normal values are obtained. Preferably, the cortisol agonist is an analogous synthetic cortisol with a glucocorticoidal and / or corticoidal mineral effect, for example, dexamethasone. The invention also relates to a diagnostic system for the purpose of diagnosing the metabolic syndrome, comprising a cortisol agonist of a dose described above, and an agent for measuring the content of cortisol in saliva or serum.
DESCRI PTION OF DIAMETERS
Figure 1 shows the hormone signal axis along the brain-hypothalamus-pituitary-adrenal. Figure 2 shows cortisol readings in the serum after different doses of dexamethasone given to two groups of individuals, divided according to their fat distribution in the body.
DESCRI PTION OF THE I NVENTION
The purpose of the invention is the novel medical use of cortisol agonists, which herein refer to all synthetic cortisol agonists with glucocorticoidal and / or mineral corticosteroid effects. The novel medical use is through a diagnostic preparation to diagnose the metabolic syndrome and related conditions, such as obesity in the belly, insulin resistance, a high content of fat in the blood and a high blood pressure. The invention emanates from the hypothesis that during chronic negative tension, the hormone signal axis along the hypothalamic-pituitary-adrenal brain is reinforced, which secondarily probably leads to a down regulation of GR receptors (glucocorticoids ) -and / or MR (corticoidal mineral) - (see Figure). This in turn can lead to a vicious circle where the inhibitory effect of GR and / or MR secretion on CRF (cartocotropin release factor, a hypothalamus signal substance that stimulates the release of ACTH from the pituitary gland), could attenuate. As a result of this, the inhibition of cortisol through the GR- and / or M R receptors could be weakened and in this way, in each given stress situation it could lead to a higher cortisol secretion (see Figure). In an attempt to test the previous hypothesis, there is a scientific method that measured the basal concentration of cortisol and then given dexamethasone, a synthetic cortisol analog, which is a synthetic hormone substance with the effect of cortisol, at varying doses. The idea was that patients with low regulation GR and / or MR receptors could have their cortisol production less inhibited when dexamethasone (an example of a synthetic cortisol analog) is used at low doses, particularly when compared to the initial value , which can usually be a little higher in healthy people. The lower inhibitory effect in this way is related to the production of non-inhibited cortisol. When tested on people with normal weight, overweight people and people with obese tummy, it was found that the hypothesis is in accordance with reality. Obesity in the belly is obesity within the abdominal cavity in contrast to general obesity. Those individuals with an obese belly also had baseline cortisol values significantly lower at 8:00 hours when compared with cortisol in the serum with the control. Here, values above or equal to 400 nmol / 1 were considered normal values. The analysis group was 22 men with an age between 40 and 60 years. Eight of them were not obese according to BM I (body mass index) in a definition of <25 kg / m2 and 14 were obese with a BM I of > 25. 12 men had a WHR (waist hip ratio) < 1 .0 and 10 had an XH R > 1 .0. Dexamethasone was administered in a dose of 0.05,
0. 125, 0.25 and 0.5 in an arbitrary order with intervals of 1 week. Dexamethasone was taken at 22:00 hours and the cortisol content was measured at 8:00 the next morning. To establish the inhibitory effect for at least 3 hours and at most 24 hours must pass between the consumption of the cortisol antagonist and the measurement of the cortisol content. Figure 2 shows the differences (delta values) between the cortisol content measured and the basal values (not inhibited) after different doses of dexamethasone. A comparison was made between men with WH R < 1 .0 (open squares) and men with WHR > 1 .0 (full squares). Individuals with an obese belly in this manner showed significantly lower inhibition through dexamethasone (a synthetic cortisol analogue) at low doses. The effect was found in doses between 0.05 and 0.5 mg. This should be compared with the aforementioned test where no effect could be established at a dose of 1 mg of dexamethasone. Thus, it has now been surprisingly shown that low doses of dexamethasone obtain a significantly lower inhibition of cortisol self-production by individuals with an obese belly. For individuals with normal weights, and those with general overweight, but without obesity in the womb, inhibition of self-production of cortisol was obtained at a dose of 0.05 mg and continuously up to a maximum inhibition at 1 mg (for some also at 0.5 mg ). For individuals with obesity in the "dangerous" womb, it was found that the inhibition can not be measured until the dose was increased to 0.25 mg. Then, the maximum inhibitory dose was the same as for healthy individuals, that is, the maximum inhibition in the range of 0.5-1 mg. This means that for individuals with obesity in the womb, the inhibition curve is shifted to the right. It was found that the critical doses with significant differences in the material (approximately 20 individuals) are 0.125 mg and particularly 0.5 mg (the most different difference with this dose). During the first moment, it was also shown that there is a so-called dose-response curve for the dexamethasone test, by which differences can be detected between individuals at risk of developing the metabolic syndrome and / or ndividuals with one or more Risk factors / conditions related to the metabolic syndrome, when compared with healthy individuals. The doses mentioned above were maintained for the substance tested, dexamethasone. The effective dose varies for different cortisol antagonists. Crude conversions of effective doses of the different cortisol agonists are found in the literature, for example in FASS. The cortisol agonist, which in this investigation was dexamethasone, was administered as a tablet. The cortisol content was measured twice in the serum.
In the same investigation, the cortisol content was a parallel measure in saliva for a small number of individuals. This was done with a normal tablet (Salivette), which the patient kept in his mouth for about 45 seconds and then sealed in a simple and normal way. The tablets were then analyzed for cortisol content. In this test, then a good correlation was found between the cortisol content in the serum and in the saliva. The invention also relates to a diagnostic system comprising a cortisol agonist as described above, and means for measuring the content of cortisol in saliva or serum in order to measure the inhibitory effect on cortisol production. Such means for measuring cortisol content are available as normal devices. The diagnostic system may also involve means to measure the basal cortisol content since, as shown above, it has been established that individuals with obese tummy have significantly lower basal cortisol values (less than 400 nmol / l in the serum). compared to the normal population. Measuring at least two different doses of the cortisol agonist (in the case of dexametasone at 0.125 and 0.5 mg), and constructing an inhibitory curve taking into account both the measured inhibitory effect and the basal cortisol concentration measured, a test of very specific diagnosis.
Claims (9)
1. The novel use of the cortisol agonistic diagnostic system for the diagnosis of the metabolic syndrome and related conditions such as obese belly, insulin resistance, including the increased risk of developing senile diabetes, that is, type II diabetes, a high content of fat in blood and high blood pressure.
2. The novel use, according to claim 1, characterized in that the cortisol agonist is a synthetic cortisol analog having a glucocorticoid and / or mineral corticoid effect.
3. The novel use, according to claim 2, characterized in that the cortisol agonist is dexamethasone.
4. The novel use, according to claim 3, characterized in that the dose of dexamethasone is in the range of between 0.05 and 0.5 mg.
5. The novel use, according to claim 4, characterized in that the dose of dexamethasone is in the range of 0.125 to 0.5 mg.
6. The novel use, according to any of the preceding claims, characterized in that the diagnostic system involves at least two different doses of the cortisol agonist.
7. The novel use, according to claim 6, characterized in that the two doses of dexamethasone are 0.125 and 0.5 mg.
8. The novel use, according to any of the preceding claims, characterized in that it comprises means for measuring the content of cortisol in saliva or serum, for the purpose of measuring the inhibitory effect on the self-production of cortisol.
9. The novel use, according to claim 8, characterized in that the diagnostic system comprises means for measuring the basal cortisol content.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9501991A SE505391C2 (en) | 1995-05-30 | 1995-05-30 | Use of cortisol agonists to prepare a system for diagnosing the metabolic syndrome |
| SE9501991-5 | 1995-05-30 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| MX9709234A MX9709234A (en) | 1998-10-31 |
| MXPA97009234A true MXPA97009234A (en) | 1999-01-11 |
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