FR2619009A1 - ANTI-HYPERLIPEMIC AGENT - Google Patents

Abstract

Anti-hyperlipemic agent characterized in that it has as active principle dehydroepiandrosterone or its derivative; said derivative is an ester of the third hydroxyl of dehydroepiandrosterone; said derivative is dehydroepiandrosterone conjugated with sulfuric acid. The invention relates to an anti-hyperlipemic agent.

Description

Anti-Hyperlipemic Agent Background of the Invention

  The invention relates to an anti-hyperlipemic agent having dehydroepiandrosterone (DHA) as the active component having antihyperlipemic effects and more particularly relates to an antihyperlipemic agent for use

  as a medicine or for the prevention of

  in human or animal cases.

  Normal values of the concentrations

  Liquid and lipoprotein in humans are as shown in Table 1 below:

  Table 1: Normal values of serum concentration in

  quides and lipoproteins in humans

  - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

  Type Normal Values Total Cholesterol 115 - 211 mg / dl Triglycerides 34 160 mg / dl Phospholipids 159 - 299 mg / dl Chylomicrons 0 (fasting) VLDL 20 400 mg / dl (VLDL-Chol.) Less than 30 mg / dL LDL 200 - 400 mg / dl (LDL Chol.) Less than 170 mg / dl HDL Male 125 - 425 mg / dl (HDL - Chol.) 37 57 mg / dL Female 250 - 650 mg / dL (HDL - Chol.) 36 - 70 mg / dl Lipoprotein fraction a-lipoprotein (HDL) 20.0 - 50.0% prep-lipoprotein (VLDL) 8.5 - 19.9% P-lipoprotein (LDL) 37.1 - 54.7%

  The physico-chemical properties and the com-

  position of these lipoproteins are as shown in Table 2 below: Hyperlipemia is the disease in which

  an excess of lipids exists in the blood due to a

  exaggerated uptake of lipids like cholesterol

  terol, neutral fats or the like .. or due to an abnormal lipid metabolism. Hyperlipemia is a

  general name applied for all these diseases.

  The term "hyperlipemia" is further divided into: - hyperchylomicronemia hypercolesterolemia - hypertriglyceridemia

  according to the types and concertrations in lipids.

  T a b 1 e a u 2: Physicochemical Properties and Lipoprotein Lipoprotein Compositions

  __________________________________________________________________________ ________________

Chylomicrons VLDL IDL LDL HDL2 HDL3

  __________________________________________________________________________ ______________________________________

  Specific gravity <0.96 0.96-1.006 1.006-1.019 1.019-1.063 1.063-1.125 1, 125-1.21 (g / ml) Diameter 800-10000 300-750 220-300 190-220 85-100 75- 85 Electrophoresis origin pre-p- (medium band) pa a1 Composition Triglyceride (TG) 85 55 24 10 5 4 Cholesterol Ester (CE) 5 12 33 37 18 12 Free Cholesterol (FC) 2 7 13 8 6 3 Phospholipids (PL) 6 18 12 22 29 23 Protein 2 8 18 23 42 58 VLDL: Very low density lipoprotein IDL: Intermediate LDL lipoprotein density: Low density lipoprotein

  HIIDL: High density lipoproteins.

  N oo C> T ab 1 water 3: Classification and Aspects of Hyperlipemia (WHO Classification) Lipid Concentration Type Image of Electrophoresis Condition Cholesterol Triglycerides C / TG Causes lipoproteins on paper (220mg / dl) (120mg / dl) filter lipid I Increase Hyperchylo- or <-> <0.2 Decrease in the capacity of micronemie chylomicrons. Decreased Chylomicrons Lipase Activity IIa Increased f- Hypercholes- <-> or Catabolic Disorders of P-LDL teremia p-lipoprotein IIb Augmentation P- Hypercholes-> 0.5 Increased synthesis

  LDL-P and TG-teremia and decrease in catabolite

  Prep-VLDL prep- Hypertriglylism- Increase in

  ceridemia tabolism lipoproteins.

  III Increase Hyperchloles- = 2 Existence of abnormal lipoproteins of IDL Pteremie. Disorder pre-p large Hypertrigly catabolic ceridemia

  IV Increase Hypertrigly- <-> oul Catabolic disorder of TG.

  VLDL pre P-ceridemia Partial increase in synthesis V Augmentation Hyperchyl- Decrease in activity

chylomicronemic urinary enzymes.

  crons and Hypercholes- 0.15 <0.6 Catabolic Disorder of VLDL Teremia TG

Hypertrigly--

  ceridemia o In general, IIa> IV> IIb 'o WHO (World Health Organization) classifies hyperlipaemia into 6 types as shown in Table 3 above according to the nature of the lipoproteins. Hyperlipemia is usually observed in middle-aged or older people in most

  case and the lipids are deposited on the arterial walls.

  or in the connective tissue. On the other hand cases of hyperlipemia found in younger people

  is primarily a metabolic disorder of a hereditary nature

  and this is called "familial hyperlipemia".

  Hyperlipemia is closely related to sclerosis

  arterial disease and very often leads to pulmonary sclerosis

  the aorta, coronary arteries, basilar artery, and others. It occurs frequently in

  coronary arteries and causes angina pectoris

  trine and myocardial infarction. In addition, she

  also leads to cause cholelithiasis.

  As already described, the hyperlipene

  causes vascular disorders such as sclerosis

  arterial. As a result, it is necessary to

  take therapeutic measures to reduce each

any of these causes.

  For this purpose, the methods of

can be divided as follows.

  1. In order to treat food hyperlipemia

  re, which is caused by an excessive recapture of

  or cholesterol, it is recommended to carry out

  a food therapy by restriction of

  physiotherapy by increasing the consumption of

  if these methods of treatment do not

  do not bring favorable results, therapeutic

by medication is recommended.

  2. To treat familial hyperlipemia of hereditary nature, manifesting a disorder in the lipid metabolism enzyme, apoproteins or mechanism of receptors, drug therapy - direct drug delivery

- is started.

  3. To treat secondary hyperlipemia

  which is caused by other diseases like nephrosis

  whether, diabetes or other, therapeutic methods to eliminate the causes of such diseases should

  be put in place to improve pathological disorders.

of these basic diseases.

  The drugs to be used in the therapy

  ticks include drugs that inhibit

  synthesis of cholesterol and the drugs that develop

  loppent the metabolism of lipids. As an inhibitor

  absorption, there is cholestyramine made of anion exchange resin, melinamide derived

  of oleic amide and soyasterol, a

  saponifiable soybean oil. As an inhibitor

  of biosynthesis, base-based preparations,

  brobucol and clofibrate are widely known.

  On the other hand, among the substances that develop

  metabolism of lipids, heparin, sulfuric ester

  that dextran are known. They increase the activity of lipoproteinelipase and increase the effects

catabolic lipoproteins.

  Nevertheless, it is also known that these drugs cause side effects, such as

  moderate symptoms in the digestive system (inhibi-

  cholesterol uptake), hepatic

  ticks, disorders of the digestive tract, lithiasis

  bile (inhibitor of cholesterol biosynthesis).

  Current inventors have implemented biochemical research on hyperlipemia and have

  found that DHA and DHA-sulfate (DHA-S) have ef-

  excellent anti-hyperlipemic drugs. In addition, the inventors have manufactured preparations based on DHA

  to carry out the therapeutic experiments

  on human subjects and to evaluate the effects

  side effects by administering the medications

  to subjects with hyperlipemia. The results of these experiments revealed that DHA-based compositions have the effect of

  to reduce hyperlipemia, strengthen the vasculature

  and remove thrombocytes adherent to the vessel wall. In addition no side effects like

planned was not recognized.

  The invention is characterized in that an anti-hyperlipemic agent has dehydroepiandrosterone or its derivative as active principle; said derivative

  is an ester of the third hydroxyl of dehydro-

  piandrostérone; said derivative is dehydroepiandros-

  terone conjugated with sulfuric acid; said déhy-

  droepiandrosterone or said derivative is administered to

  the man; said dehydroepiandrosterone or said dehydroepiandrosterone

  vé is administered to animals kept at home or

  in a zoo; the dosage of said dehydroepiandros-

  terone or said derivative, is 25 to 75 mg / day

  the man; said dehydroepiandrosterone or said dehydroepiandrosterone

  vé, are administered orally; said dehydroe

  piandrosterone or this derivative are presented in the form of tablets, capsules, granules or powders.

BRIEF DESCRIPTION OF THE DRAWINGS:

  - Figure 1 shows the synthesis scheme of steroids

  and Figure 2 shows the metabolic mechanism of dehydroepiandrosterone.

  DETAILED DESCRIPTION OF THE INVENTION

  The present invention relates to an anti-hyperlipemic agent having DHA or its derivative as active ingredient. In this case, the term "DHA derivative" includes sulfuric acid-conjugated DHA or the like. As mentioned here the DHA is

  a chemical substance already known. This is one of the hor-

  mones steroids produced and secreted by the cortex

  adrenal. As a derivative of DHA, there is a

  ter of the third hydroxide on DHA. A typical example

  is the product of conjugation of DHA with sulphate

  Furic who is an urophanic type of DHA. Nevertheless, this term is not limited to this example and derivatives

  synthesis can also be used.

  In the following, the properties of DHA and

  DHA sodium sulfate which are the effective components

  these according to the present invention will be described.

1. Dehydroepiandrosterone (DHA):

  Chemical name: 3p-hydroxy-5-androsten-

  17-one Molecular Formula: C9H2802 Molecular Weight: 288.43 Structural Formula H0 Melting Point: Needle Crystals 140 - 141 "C Crystals in Sheets 152 - 153 C Properties Colorless crystals or crystalline powder odorless Solubilities very soluble in benzene, l alcohol and ether;

very slightly soluble in chloro-

  form and water-insoluble petroleum ether 2. Dehydroepiandrosterone-sodium sulfate (DHA-S):

  Chemical name 3p-hydroxy-5-androsten-17-one-

  sodium sulfate (dihydrate) Molecular Formula Cl9H27NaO5 2H20 Molecular Weight 426.50 Structural Formula: o0 2H20 NaO3SO Melting Point Approx. 154 C (Decomposition) Properties colorless crystals or crystalline powder without odor or

bitter taste.

  Solubilities a little soluble in metha-

  nol, very slightly soluble in water, slightly soluble in

anhydrous and essential ethanol

insoluble in

acetone, ether, chlorine

form or benzene.

pH 4.0-7.0 (0.5% sol, weight

flying in the water).

  Normal doses of DHA or its derivative based on this invention are 25 to 75 mg / day by oral administration. The dosage can be

  adjusted according to sex, age, degree of ob-

sity and other symptoms.

  As pharmaceutical compositions for

  oral administration, the product can be prepared.

  in the form of tablets, capsules, granules,

  powder or others. The compositions can be manufactured

  according to the normal pharmaceutical procedure. The

  rough synthesis scheme of the steroids of the cor-

  Adrenal tex is shown in Figure 1. Approximately different steroid hormones synthesized biochemically in the adrenal cortex have been isolated so far. As shown in Table 4, they are roughly divided into glucocorticoids biochemically related to carbohydrate metabolism

  (eg cortesol), mineralocorticoid

  related to electrolyte metabolism (eg

  aldosterone) and androgens (DHA and conjugated DHA).

fortified with sulfuric acid DHA-S).

  DHA is produced from DHA-S. For

  this reason DHA-S is called hormone-type storage

  Kage. DHA is a steroid that can be bio-origin

  synthetic androgenic hormones-testosterone and estradiol, but testosterone and estradiol:

Table 4:

  Steroids secreted by the human adrenal cortex Group Compounds Average quantity secreted per day in adults Cortisol 15 - 20 mg Glucocorticoid Corticosterone 2 - 5 mg Aldosterone 50 - 150 mg Mineralocorticoid 11-deoxycorticosterone Trace Dehydroepiandrosterone 15 - 20 mg Androgens / \ 4-androstenedione 0 - 10 mg 11p-OH androstenedione 0 - 10 mg Pregnenolone 0.5-0.8 mg Progestins 17-OH Pregnenolone 0.2-0.4 mg Estrogens Estradiol Trace are synthesized in the adrenal cortex only in small amounts. DHA has very little effect as a sex hormone. It produces effects on lipid metabolism and on the metabolism of

  protein and also influences metabolism.

  salts such as phosphoric acid, potassium

  sium, sodium. It is excreted by urine as DHA-S as shown in Figure 2. It is also excreted as androsterone or etiocholanolone conjugated with sulfuric acid or

  glucuronic acid via the andros-

  ténedione. All these substances can be dosed as 17 ketosteroids (Cetosteroids). In the case of women (non-pregnant), most of these 17

  ceto-steroids are considered to derive from

adrenal tex.

  In the case of man 2/3 to 3/4 of these derive from the adrenal cortex while the 1/3 or the

  1/4 remaining is from the testicles.

  It is experimentally demonstrated that metabolic products of DHA as excreted

  in the urine (17-keto-steroid urinary) by the

  lades having hyperlipemia, are in small quantity.

  When diabetes or other diseases are combined with obesity, they are found in extremely small amounts. DHA and DHA-S (a form of DHA storage) are abundant in the blood of subjects

  younger age group (aged 20 to 30), but the

  progressively decrease as they age. On the contrary, cortisol is secreted most of the time in a constant amount (15-20 mg

  per day) regardless of age, and 17-

  hydroxycorticosteroids (17-OHCS) are excreted in

urine as metabolites.

  DHA inhibits lipid synthesis and

  cholesterol and blood lipids while excessive secretion of cortisol in connection with excessive secretion of insulin compared to

  it increases the synthesis of lipids.

  As a consequence when the secretion of DHA

  is diminished because of age or for other reasons.

  cortisol and insulin can no longer be refuted or inhibited and lipids begin to accumulate gradually in fatty tissues. This leads to obesity, produces disorders in

  production and secretion of insulin and final-

  induces the onset of diabetes.

  DHA has the effect of inhibiting and regulating

  the production of insulin and cortisol at the same time.

  In addition, it prevents blood clotting and

aggregation of platelets.

  By oral administration, DHA reaches the intestine and is converted to DHA-S. It is then transported to different tissues in this form and

  is converted back into DHA. This inhibits the activity of the

  zyme glucose-6-phosphate dehydrogenase (G6 PDH) which is closely connected to steatogenesis. It is

  this provides the anti-lipemic effects.

  Another excellent feature of DHA is that no side effects have been observed during

this experimentation.

  The anti-hyperlipemic effects of DHA occur not only in humans but also in animals kept at home or in a zoo. It is useful as an anti-hyperlipemic agent for

  both for human and animal cases.

  DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS:

  In the following examples of embodiments

  anti-hyperlipemic agent according to the present invention.

  vention, animal experiments,

  Acute toxicity and clinical trials are described.

  It must be understood that the present invention is not

  not limited to the precise details of such a description.

tion.

  Exemplary embodiment 1: DHA tablets Composition of one tablet: DHA (dehydroepiandrosterone) 25 mg Lactose 80 mg Starch 12.5 mg Polyvinylpyrrolidone sold under the trade name K 30 5 mg Magnesium stearate 2.5 mg

- - - - -

  Total 125 mg method of making tablets: Process by wet granulation: Tablet diameter: 7 mm

Appearance: white tablets.

  Exemplary embodiment 2: DHA-S tablets Composition of the tablet DHAS (sodium dehydroepiandrosterone sulfate) 35 mg Lactose 70 mg Starch 12.5 mg Polyvinylpyrrolidone sold under the trade name K 30 5 mg Magnesium stearate 2.5 mg Total 125 mg Method tablet production method: wet granulation method: Tablet diameter: 7 mm Appearance: white tablet

  mg of DHA-S is equivalent to 25 mg of DHA.

  Animal test: SD adult rats (10 male and 10 female rats) were used, dividing them between a control group and a test group. Food containing DHA (0.6%) was administered to the group

  test and food without DHA was administered

  to the control group for 11 weeks. Then the

s rats were tested.

  The body composition of the rat in the group

  receiving DHA is as indicated in

5.

Table 5:

  Sex Male (n = 5) Females (n = 5) Group Group Group Group Control group treated with control treated with DHA by DHA Body weight 526 445 288 268 (g) Water (%) 58.3 62.2 60.3 64.6 Protein (%) 51.2 56.2 49.3 59.0 Fats (%) 36.8 33.2 37.4 24.0% O rO Experiments were performed on the effects of DHA for determine liver weight, G6DDH activity in liver tissue and triglycerides in serum. These results are as shown in Table 6.

Table 6:

  Sex Male Females Group Group Group Group DHA treated control group DHA Liver weight 0.45 0.77 0.37 0.51 (g) G6PH activityl 0.0486 I 0.0301 | 0,0473 | 0.0303 <(pm / g protein) | l | Triglycerides 295 215 290 190 Idu serum (mg / dlI 2 290 9 CD o ho Acute toxicity test:

  DHA was administered subcutaneously

  dermal or oral in ICR male and female mice and in SD-rats. The LD50 in mg / kg was determined. The results are provided in Table 7.

Table 7:

  Mouse Rat male female male female Subcutaneous administration 900 1, 060 1,000 1,015 Administration> 10,000> 10,000> 10,000> 10,000 oral C> 0% o / In a chronic toxicity test with mice or rats, no pathological changes

has not been observed in any case.

  Clinical Trial 1: A clinical trial was initiated in 5 subjects with hyperlipemia. Age, sex,

  blood lipids or other substances are indicated in

Bleau 8 below.

  The drug used for this test was DHA tablets prepared according to Example 1 above, each containing 25 mg of DHA. One tablet was administered at each meal, 3

  once daily, ie 75 mg of DHA administered per day.

  The period of administration varied from 3 to 5 months

  the symptoms. The use of other drugs has been

avoided during this period.

Table 8:

  Test number 1 2 3 4 5 Age 64 52 56 48 44 Sex HFHFH Total cholesterol 290 250 280 260 300 (mg / dl) _ Before Triglyceride administration (neutral fats) (mg / dl) 257 270 260 260 280 Free fatty acids 720 590 '680 580 690 p Eq / l) Total cholesterol (mg / dl) 205 230 190 210 210 After Triglyceride administration (neutral fats) (mg / dl) 150 130 140 120 150 Free fatty acids 510 430 490 450 530 (p Eq / l) Clinical trial 2: A clinical trial was performed in addition to 5 female subjects. The drugs used for this test were said tablets. One tablet was administered once a day (25 mg of DHA given per day). Table 9 below shows the results of

  this test on the improvement of blood lipids.

  As was the case in clinical trial 1 above, the use of other drugs was avoided during the

period of the test.

Table 9:

  Trial Sex Age Administration Division p-Lipopro- Trigly- Phospho- Fatty Acids Cholesterol CHOL-

  ceridin tein (PL) lipids (PL) free (NEFA) ester type HDL n Duration Day (mg / dl) (mg / dl) (mg / dl) (p Eq / ml) (mg / dl) (mg / dl)

  __________________________________________________________________________ _________________________________________

  Before administration 543 229 213 0,798 148 33

  6 Woman 24 14 ---------------------------------------------. ............

  After administration 461 147 189 0.460 141 38

* __________________________________________________________________________ _________________________________________

  Before administration 322 127 221 0.610 116 44

  7 Woman 45 60 ---------------------------------------------- -------------------------------------

  After administration 358 73 200 0.942 140 54 Before administration 494 86 261 0.110 206 53

  8 Woman 48 60 ------------------------------------------.- --------------------------------------

  After administration 469 98 198 0.319 155 43 Before administration 255 122 170 0.459 111 47 9 Female 45 76 ------------------------------ ------. -------- ._ ------ ___-_______________ - _-________ After administration 283 106 217 0,507 153 58 Before administration 596 197 237 0,136 179 51

  Woman 50 78 ----------------------------------------------- ------------------------------------

  After administration 455 154 220 0.499 190 53 o o C

  In each case, the triglyceride values

  cerides, phospholipids and the like, which have been above normal values, lowered to the normal range and DHA has been confirmed to have excellent anti-hyperlipemic effect.

  As described above when the anti-

  hyperlipemic approach based on the present invention is

  administered to patients, the active component DHA or

  its derivative increases the metabolism of lipids and

  malise the level of lipids in the blood. As a result

  tat, the drug strengthens the walls of the blood vessels to prevent arterial sclerosis as well as angina and myocardial infractus

in human and animal cases.

Claims (3)

R E V E N D I C A T I ONS   1 ') Antihyperlipemic agent is characterized   in that it has the active principle of dehydroepian- drosterone or its derivative.   2 ') Agent according to claim 1, characterized in that said derivative is an ester of the third   hydroxyl of dehydroepiandrosterone.   3 ') Agent according to claim 2, characterized   in that said derivative is dehydroepiandrost   conjugated with sulfuric acid.   Agent according to claim 1, characterized   in that said dehydroepiandrosterone or said   derivatives are presented in the form of tablets, sules, granules or powders.