WO1998010786A2 - Composition pharmaceutique pour le traitement du syndrome x de reaven - Google Patents

Composition pharmaceutique pour le traitement du syndrome x de reaven Download PDF

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Publication number
WO1998010786A2
WO1998010786A2 PCT/IL1997/000301 IL9700301W WO9810786A2 WO 1998010786 A2 WO1998010786 A2 WO 1998010786A2 IL 9700301 W IL9700301 W IL 9700301W WO 9810786 A2 WO9810786 A2 WO 9810786A2
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Prior art keywords
phe
lys
trp
thr
alkyl
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PCT/IL1997/000301
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English (en)
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WO1998010786A3 (fr
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Yarom Cohen
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Yarom Cohen
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Priority claimed from IL11925096A external-priority patent/IL119250A/xx
Priority claimed from IL11940396A external-priority patent/IL119403A/en
Application filed by Yarom Cohen filed Critical Yarom Cohen
Priority to AU41339/97A priority Critical patent/AU4133997A/en
Publication of WO1998010786A2 publication Critical patent/WO1998010786A2/fr
Publication of WO1998010786A3 publication Critical patent/WO1998010786A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K38/31—Somatostatins

Definitions

  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising as active ingredient a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin, for the treatment of syndrome X of Reaven (also called "Hyper Insulinemia syndrome" or "The Deadly quartet”) .
  • Somatostatin and its analogs are known for the treatment of the reduction of the secretion of Insulin caused by insulimonas. Moreover, they are known for the treatment of certain tumors, gastrointestinal diseases, etc. However, their effectivity for the reduction of the resistance to insulin has so far not been known.
  • Diazoxide, Cyclothiazide and Metformin achieve the reduction of the resistance to Insulin.
  • Metformin is used in the treatment of Diabetes and reduces risk factors in carbovascular diseases in NIDDM.
  • Diazoxide, Cyclothiazide and Metformin have the following formulae: a. Diazoxide: 7-chloro-3-methyl-24-l,2,4-benzothio- diazine' 1,1-dioxide. b. Cyclothiazide: 3-bicyclo[2.2.1]hept-5-en-2y1-6-chloro-
  • Syndrome X includes, inter alia, the following risk factors: a. excessive blood pressure; b. dislipidemia, i.e. increase of the amount of Triglycerides in the blood, reduction of the amount of HDL and increase of the amount of LDL, c. excessive blood coagulation due to Plas inogen Activator Inhibitor-1 (PAI-1) increased in the blood; d. central obesity; e. Glucose intolerances - from ocult Diabetes to overt Diabetes f. increase of Insulin in the blood, i.e. the pancreas secretes more Insulin in order to overcome high Insulin resistance.
  • PAI-1 Plas inogen Activator Inhibitor-1
  • Ischemic Heart disease e.g. Angina Pectoris, Myocard Infarct; Cerebral Vascular Diseases and the like.
  • the present invention thus consists in pharmaceutical preparations for the treatment of the risk factors of syndrome X of Reaven comprising as active ingredient a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazi- deor one of its analogs (as herein defined) and metformin.
  • the present invention also comprises the use of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazideor one of its analogs (as herein defined) and metformin in the preparation of a pharmaceutical preparation for the treatment of the risk factors of syndrome X of Reaven.
  • Analogs of somastostatin in connection with the present invention mean any analog compound of somatostatin which biologically activate one or more somastostatin receptors. Said receptors cause the reduction of the resistance to Insulin and thus enable the combined treatment of all risk factors of syndrom X of Reaven and are thus effective in primarily & secondary preventing and/or treating Ischemic Heart disease, such as, Angina Pectoris, Myocard Infarcts ; Cerebral Vascular Diseases, etc.
  • receptors there should be mentioned, inter alia, the following human somatostatin receptors, which are described in Steven W.J. Lamberts, et al. 1996. Octreotide.. The New England Journal Med. Jan. 25. pp. 246-54. These receptors are:
  • Aspartic acid (Asp) is located in the third loop outside the cell.
  • receptors 2 and 5 which are especially important in reducing the Insulin resistance are receptors 2 and 5, also but less receptor 3.
  • Receptors 1 and 4 are less important in this respect.
  • somatostatin is not always satisfactory as it is effective only for a short time. Therefore the use of Octreoide, the most known analog of somatostatin or of another long acting Somatostatin, is preferred.
  • the analogs of somastostatin should comprise the chain D- Trp-Lys .
  • Said chain constitute the critical core of the active analogs and is essential for the activation of the receptors.
  • Suitable analogs of somatostatin being part of the pharmaceutical composition according to the present invention are, for example, : 1. Octreotide. 2'. Vapreotide.
  • Cyclopeptide somatostatin analogues selected among : Cyclo[Pro-Phe-D-Trp-Lys-Thr-Phe] Cyclo[N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe] Cyclo[Pro-Ala-D-Trp-Lys-Thr-Phe] Cyclo[Pro-T ⁇ r-D-Trp-Lys-Thr-Phe] Cyclo[Pro-Phe-D-Trp-Lys-i-aminobutyric-Phe] Cyclo[N-Me-Ala-Phe-D-Trp-Lys-Thr-Phe] Cyclo[Pro-Phe-D-Trp-Lys-Val-Phe] Cyclo[D-Ala-D-Phe-D-Trp-L-Lys-D-Thr-N-Me-D-Phe] 5
  • X is H-(Aeg) m -Cys- or H-(Aeg) m -Ala-Gly-Cys-,
  • Y is -Cys-(Aeg) n -OH or
  • X and Y taken together are a 2-aminoethyl-glycyl group in the ring position and m and n are 0, 1, 2, provided that m and n are at least 1, and their cyclic disulfide derivatives.
  • Bmp represents the desa inocysteine radical
  • X represents Asn
  • trp represents D-Trp that may be substituted in the benzene ring by a halogen atom
  • Y represents the radical of an alpha-(lower alkyl) amino- (lower alkyl) -carboxylie acid having a minimum of 4 and a maximum of 8 carbon atoms, in which the two lower alkyl radicals can be connected to one another witha single C-C bond, an oxygen atom or a sulphur (II) atom.
  • Trp represents L-Trp or D-Trp, in which the benzene ring may be substituted by a fluorine atom
  • Gaba(Ar) represents the residue of a -aminobutyric acid substituted by a cyclic hydrocarbyl radical Ar selected from the group consisting of cyclohexyl; phenyl optionally substituted by halogen, nitro or phenoxy; and naphthyl optionally substituted by halogen. 25.
  • R 13 is Lys or des R 18 , R 19 is Asn or
  • R 26 , R 27 is Ser or D-Ser and R 28 is D-Cys or Cys . 26 .
  • R 18 is Lys or des R ⁇ a
  • R 19 is Asn or des
  • R 19 , R 25 is Phe or Tyr, R 26 is Thr or des R 26 ,
  • R 27 is Ser or D-Ser and R 23 is D-Cys or Cys, or the linear version thereof where the disulfide bridge is replaced by hydrogen.
  • R 27 A cyclic hexapeptide of the formula -X - Phe-D-Trp-Lys-Y-Phe ⁇ i I in which X represents the radical of an L-aminoacid of the formula
  • a and B are identical or different and denote alkyl having 1 to 3 carbon atoms, or A and B together represent a saturated, unsaturated or aromatic monocyclic or bicyclic structure having 3 to 6 carbon atoms, n denotes 0 or 1, and
  • Y represents an aliphatic or aromatic L-aminoacid the side- chair of which can be hydroxylated, said amino acid being selected from the group consisting of L-alanine, L-serine, L-valine, L-leucine, L-isoleucine, L-phenylalanine and L- tyrosine.
  • Acyl is a group of formula RXo- wherein R 1 is C 120 alkyl or phenyl; a group of formula R ⁇ S0 2 - wherein R 11 is C 120 - alkyl, phenyl or tolyl; a group
  • R IV R ⁇ and R IV are each independently hydrogen or C 1-l0 alkyl; or biotinyl, A is hydrogen or C ⁇ alkyl,
  • >N-CH(Z)-CO- is an (L) - or (D) -phenylalanine residue optionally ring-substituted by N0 2 , or an (L) or (D)-norleu- cine residue, whereby
  • Z in * ⁇ N-CH(Z) -CO- represents the remainder of said residue
  • B is -Phe- optionally ring-substituted by N0 2
  • F is a group of formula
  • R is hydrogen or a group of formula
  • R 5 is CH 3 CH (OH) - , i-butyl or benzyl X is a group of formula -COOR ! , -CH 2 OR 2 or R ⁇
  • R x , R 6 and R 7 are each hydrogen or C ⁇ alkyl
  • R 2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, the group -CH(R 5 )-X having the (D)- or (L) -configuration
  • Y x and Y 2 are each hydrogen or together represent a direct bond, whereby the residue resides in the 2- and 7-position each indepen-dently have the (L)- or (D) -configuration, and with the proviso that: i) (L)- and/or (D) -cysteine residues are present at the 2- and 7-positions only.
  • A is C 1 . 12 alkyl , C 7 . 10 phenylalkyl or a group of formula RCO- , whereby i) R is hydrogen, c ⁇ n a-lkyl , phenyl or
  • RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by halogen and/or C ⁇ alkyl , b) H-Asn- , or c) H-Nle-Asn- , the ⁇ -amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally ono- or di-C 1 12 alkylated,
  • A' is hydrogen or, when A is C 1 12 alkyl or
  • 10 phenylalkyl, B is -Phe-optionally ring-substituted by halogen and/or
  • C x 3 alkyl is - (L) - or - (D) -Trp- optionally ⁇ -N-methylated and optionally benzene-ring-substituted by halogen and/ or
  • D is -Lys- optionally ⁇ -N-methylated and optionally
  • E is -Thr- or -Ala- each in (D) - or (L) -form and each being optionally ⁇ -N-methylated,
  • F is a group o or
  • R x is hydrogen or C 1 alkyl
  • R 2 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester
  • R 3 is hydrogen, C ⁇ alkyl, phenyl or C 7 . 10 - phenylalkyl
  • R caution is hydrogen, Cj 3 alkyl or, when R 3 is hydrogen or methyl, also a group of formula -CH(R S )-X
  • R 5 is hydrogen, -(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH,
  • benzyl X is a group of formula -COO ! , -CH 2 OR 2 or
  • R : and R 2 have the meanings given above, R e is hydrogen or C h alky1 and R 7 is hydrogen, C 1 alkyl, phenyl or C 7 . 10 phenylalkyl, the group -CH(R 5 )-X having the D- or L- configuration, and Y t and Y 2 are each hydrogen or together represent a direct 11 bond, whereby the residues in the 1- and 6-position each independently have the L- or D-configuration. 30.
  • A is C x 12 alkyl, C 7 10 phenylalkyl or a group of formula RCO-
  • R is hydrogen, C t u alkyl, phenyl or C 7 10 phenylalkyl or ii) RCO- is a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, No 2 , NH 2 ,
  • Y j and Y 2 represent together a direct bond or each of Y : and Y 2 is independently hydrogen or a radical of formulae (1) to (5) .
  • R a is methyl or ethyl
  • R b is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 e is (Ci 6 ) alkyl
  • R d represents the substituent attached to the ⁇ -carbon atom of a natural or synthetic ⁇ - a ino acid (including hydrogen)
  • R e is (Cj. 5 ) alkyl
  • R a ' and R b ' are independently hydrogen, methyl or ethyl
  • R 8 and R 9 are independently hydrogen, halogen, (C 1 3 ) alkyl or (C 1 3 )alkoxy,
  • P is 0 or 1
  • q is 0 or l
  • r is 0, 1 or 2
  • B is -Phe- optionally ring-substituted by halogen
  • C is (L)-Trp- or (d)-Trp- optionally ⁇ -N-methylated and optionally benzene-ring-substituted by halogen, N0 2 , NH 2 OH, C x 3 alkyl and/or C x 3 alkoxy,
  • D is Lys, Lys in which the side chain contains O or
  • E is The, Ser, Val, Phe, lie or an aminoisobutyric or aminobutyric acid residue
  • G is a group of formula
  • R 7 is hydrogen or C t 3 alkyl
  • R 10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester, is hydrogen, C x 9 alkyl, phenyl or C 7 10 phenyl-alkyl
  • R 12 is hydrogen, C x 3 alkyl or a group of formula -CH(R 13 )-X 1 ,
  • Ri is CH 2 OH, - (CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, or -CH(CH 3 )OH or represents the substituent attached to the a- carbon atom of a natural or synthetic ⁇ -amino acid (including hydrogen) and
  • X is a group of formula -COOR 7 , -CH 2 OR 10 or
  • R 7 and R l0 have the meanings given above, R is hydrogen or C L 3 alkyl and R 15 is hydrogen, C x 3 alkyl, phenyl or
  • R 16 is hydrogen or hydroxy, with the proviso that when R 12 is -CH(R 13 )-X ! then R u is hydrogen or methyl, wherein the residues B, D and E have the L-confi- guration, and the residues in the 2-and 7-posi- tion and any residues Y 4) and Y 2 4) each independently have the (L)- or (D)- configuration.
  • Y is in d epen d ently of the other, is C 1 5 each of R x and R 2 alkyl, b enzyl, benzyl having one or two C1 5 alkyl, halogen, hydroxy, amino, nitro, and/or C, . 5 alkoxy substituents, or Ci.5 alkyl substituted with 5- or 6 - me b ere d heterocyclic ring; R 3 is 3-indolymethyl, either unsubstituted or having C s alkyl, C x 5 alkoxy or halogen substitution;
  • R Planar surface potential, C s hydroxyalkyl, benzyl, carboxy- (C x 5 alkyl) , amino (C 1 5 alkyl) or benzyl having a C x 5 alkyl, halogen, hydroxy, amino, nitro and/or C L 5 alkoxy substituent;
  • R 5 is Cj 5 alkyl, benzyl, or benzyl having a
  • A is C ⁇ 12 alkyl, C 7 10 phenylalkyl or a group of formula RCO-, whereby i) R is hydrogen, C x ;1 alkyl, phenyl or C 7 10 phenylalkyl, or ii) RCO-is a) an L- or D-phenylalanine residue optionally ring- substituted by F, Cl, Br, N0 2 , NH 2 , OH, C x 3 alkyl and/or C x 3 alkoxy b) the residue of a natural ⁇ -amino acid other than defined under a) above -or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, the ⁇ -amino group or amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono
  • A' is hydrogen or, when A is C ⁇ 12 alkyl or C 7 10 phenylalk- also C x 12 alkyl or C 7 10 phenylalkyl, Y j and Y 2 represent together a direct bond or each of Y ; and Y 2 is independently hydrogen or a radical of the formulae -CO- -CO-NHR r n
  • R a is methyl or ethyl
  • R b is hydrogen, methyl or ethyl m is a whole number from 1 to 4 n is a whole number from 1 to 5 R c is (C 1-6 ) alkyl
  • R d represents the substituent attached to the ⁇ -carbon atom of a natural ⁇ -amino acid (including hydrogen)
  • R e is (C ⁇ s ) alkyl
  • R a ' and R b ' are independently hydrogen, methyl or ethyl
  • R 8 and R are independently hydrogen, halogen, (C 1 ) alkyl or ( C x . 3 ) alkoxy, p is 0 or 1, q is 0 or 1, and r is 0, 1 or 2,
  • B is -Phe- optionally ring-substituted by halogen, No 2 , NH 2 ,
  • C is (L)-Trp- or (D)-Trp- optionally ⁇ -N-methylated and optionally benzene-ring-substituted by halogen, No 2 , NH 2 , OH, C j .
  • D is -Lys-, ThiaLys, F-Lys, «SF-Lys or Orn, optionally ⁇ -N- methylated, or a 4-aminocyclohexyl Ala or 4-aminocyclo- hexyl Gly residue
  • E is Thr, Ser, Val, Phe, lie or an aminoisobutyric acid residue
  • R 7 is hydrogen or C ⁇ alkyl
  • R 10 is hydrogen or the residue of a physiologically acceptable, physiologically hydrolysable ester
  • R n is hydrogen, C 13 alkyl, phenyl or C 7 10 -phenylal- kyl
  • R 12 is hydrogen, C ⁇ alkyl or a group of for ula-
  • R 13 is CH 2 OH, -(CH 2 ) 2 -OH, -(CH 2 ) 3 -OH, or -CH(CH 3 )0H or represents the substituent attached to the ⁇ -carbon atom of anatural ⁇ -amino acid (including hydrogen) and X : is a group of formula -COOR 7 , -CH 2 OR 10 or
  • R 7 and R 10 have the meanings given above,
  • R l4 is hydrogen or C h alky1
  • R 15 is hydrogen, C 13 alkyl, phenyl or C 7 . 10 phenylalkyl
  • R 16 is hydrogen or hydroxy, with the proviso that when R 12 is -CHfRj j J-X j then R is hydrogen or methyl, wherein the residues B, D and E have the L-configuration, and the residues in the 2- and 7-position and any residues
  • Y j 4) and Y 2 4) each independently have the (L)- or (D)- configuration
  • c(Spacer-Phe-D-Trp-Lys-Thr) Spacer may stand for: b) R- ⁇ -Bn-NMe-o-AMPA c) Phe-Pro
  • Analogs of Diazoxide and Cyclothiazide are compounds which affect the receptor being adenosine 5'- triphosphate sensitive K * channels.
  • Suitable analogs of Diazoxide and of Cyclothiazide are indicated, for example, in a paper of Bertolino et al., appearing in Receptor-Channels 1993 1(4) : 267-78 "Modulation of AMPA/Kainate Receptors by Analogs of diazoxide and cyclothiazide in thin slices of rat hippocampus".
  • the analogs which may be used in the pharmaceutical composition according to the present invention are not restricted to the analogs given in said paper and any other analog having the proper properties may be used.
  • the pharmaceutical preparation according to the present invention may also comprise additional compounds such as compounds having an additional pharmaceutical effect, carriers, solvents, emulgamators, etc.
  • diazoxide sometimes has undesired salt and water retention, which may be relieved by certain thiazide diuretics, e.g. 6-chloro-2H-l, 2 , 4-benzothiadiazine-7- sulfonamide 1,1-dioxide (Chlorothiazide) ; 6-chloro-3 , 4-dihydro- 2H-1, 2, 4-benzothiadiazine-7-sulfonamide 1, 1-dioxide (Hydrochlort- hiazide) ; 6-chloro-3- (dichloromethyl) -3 , 4-dihydro-2H-l, 2 , 4- benzothiadiazine-7-sulfonamide 1,1-dioxide (Trichlormethiazide) ; or 6-chloro-3 , 4-di-hydro-2-methyl-3 [(2,2 , 2-trifluoroethyl) thiome- thyl]-2H-l, 2 ,
  • the present invention also comprises a method for the treatment of the risk factors of syndrome X of Reaven by applying to a patient a pharmaceutically effective dosage of a pharmaceutical preparation according to the present invention comprising a pharmaceutically effective dosage of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazide or one of its analogs (as herein defined) and metformin.
  • a pharmaceutically effective dosage of a pharmaceutical preparation comprising a pharmaceutically effective dosage of a compound selected among somatostatin or one of its analogs (as herein defined) , diazoxide or one of its analogs (as herein defined) , cyclothiazide or one of its analogs (as herein defined) and metformin.
  • Said dosage should preferably not exceed 50 ⁇ g/kg/day of the active ingredient (calculated on Octreotide) , preferably not exceeding 40 ⁇ /kg/day.
  • Said dosage is given in any suitable manner. It may be given as one portion once a day or even in two days or more when given in slow release form, or being divided into 3-4 dosages which are applied in equal periods of time for Octreotide, or 1 - 2 times a day for analogs with a higher t ⁇ .
  • Said dosage should preferably not exceed 8 mg/kg/day in the treatment of the active ingredient (calculated on diazoxide) in adults, and preferably not exceed 15/rag/day in the treatment of children.
  • the amount of Metformin applied should preferably not exceed 2.5 g/day divided into 2 - 3 portions.
  • Chlorothiazide 500 - 2000 mg a day;
  • Hydrochlorothiazide 50 - 200 mg a day
  • Trichloromethiazide 12.5 - 50 mg a day;
  • Polythiazide 1- 4 mg a day.
  • Said dosage has to be re-calculated on the basis of the analog being the active ingredient. Moreover, the exact dosages have to be adapted to the condition of the patients and to its specific properties e.g. weight, age, etc.
  • composition may be administered in various manners. This depends in particular on the analog being the active ingredient.
  • octreotide is advantageously injected sub-cutaneously as a saline solution.
  • Cyclo N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe is advantageously administered per os.
  • the treatment is performed, as indicated above, against the risk factors of syndrome X of Reaven, in particular against the following diseases in order to primarily and secondarily prevent and to treat:
  • Said diseases are mainly caused, as indicated above, by a high resistance to Insulin.
  • mice 60 fat male rats of the Zucker species, aged 7 weeks having an average weight of 225 g. 54 rats of same are divided into 3 groups :
  • Group A receives injections of Octreotide in a 0.9% NaCl saline solution in a high dosage (40 ⁇ g/kg/day) ;
  • Group B receives injections of Octreotide in a 0.9% NaCl saline solution in a low dosage (20 ⁇ g/kg/day) ;
  • Group C the control group, receives an injection of a 0.9% saline solution.
  • the volume of the 0.9% NaCl is identical with the volume being injected into Group A and B (At the beginning of the tests the rats have approximately the identical weight and they therefore receive the identical volume of injections) .
  • All rats receive the same amount of Food (Pair Fed) . Said amount is chosen according to the group eating the lowest amount. Thus, the influence of the drug is isolated.
  • the rats are located in a room changing light and darkness in order to simulate natural surroundings, as in general they eat in darkness.
  • the rats drink water freely.
  • the rats are weighed twice a week. At the end of the experiment the rate change of the weight is being calculated. The amount of food eaten per week is measured and the amount eaten each day is calculated. (The influence of the Octreotide on the amount of food eaten by the rats is not checked. They eat the identical amount of food.)
  • Blood is taken from the Supra-orbital sinus with slow anaesthesia with C0 2 .
  • cc of blood is put into a test tube which contains Heparin and the concentrations of Glucose and Insulin are determined;
  • cc of blood is taken from each rat and put into a test tube which contains Heparin and the concentrations of Glucose and Insulin are determined.
  • Glucose is tested by the Glucose Oxidase method in a kit of Boehringer Mannheim called Glucose GOD-Perid Method 2 x 300ml catalogue No. 124028. The test is performed on the day or the following day on which the blood is taken.
  • the Insulin is tested by the Radio Immuno Assay (RIA) by a SB INSIK-5 kit of Sorin Biomedica.
  • RIA Radio Immuno Assay
  • the method is performed by the general method known for the test of Insulin by said kit.
  • the total Cholesterol is tested by the CHOD-PAP method.
  • the total cholesterol comprises VLDL + LDL + HDL.
  • the kit with which the test is performed is manufactured by Boehringer Mannheim and the cholesterol reagent is MPA3 catalogue No. 236691 4 x 500ml.
  • VLDL is calculated by T.G./5.
  • LDL is calculated by the formula
  • LDL totaL cholesterol - (VLDL + HDL)
  • Triglycerides are being tested by the peridochrom T.G. GPO-PAP method.
  • the kit is manufactured by Boehringer Mannheim and the reagent has catalogue No. 701904 15 x 32ml.
  • the data received are worked up by standard methods for this purpose.
  • the results show that the Insulin resistance is significantly lowered, there is an increase in the level of HDL and a decrease in the level of LDL and of the Triglycerides.
  • a decrease in the rate of weight gain of young obese rats is observed, which implies a decrease in the weight of adult obese rats.
  • the Insulin resistance (Insulin Sensitivity Index) is determined using the dynamic test - the Glucose Tolerance Test (GTT) .
  • GTT Glucose Tolerance Test
  • AUC area under the curve

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Abstract

L'invention concerne une composition pharmaceutique comprenant, en tant que principe actif, un composé choisi parmi la somatostatine ou un de ses analogues, le diazoxyde ou un de ses analogues, le cyclothiazidéor ou un de ses analogues et la metformine, pour le traitement du syndrome X de Raeven (également appelé syndrome d'hyperinsulinémie ou 'quartet meurtrier').
PCT/IL1997/000301 1996-09-12 1997-09-10 Composition pharmaceutique pour le traitement du syndrome x de reaven WO1998010786A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU41339/97A AU4133997A (en) 1996-09-12 1997-09-10 Pharmaceutical composition for the treatment of syndrome x of reaven

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
IL11925096A IL119250A (en) 1996-09-12 1996-09-12 Pharmaceutical composition for the treatment of syndrome x of reaven
IL119250 1996-09-12
IL11940396A IL119403A (en) 1996-10-10 1996-10-10 Pharmaceutical composition for the treatment of syndrome x of reaven
IL119403 1996-10-10

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WO1998051331A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Somatostatine et agonistes de somatostatine servant a la reduction du poids corporel
WO1998051330A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Procede et compositions pour traiter l'hyperlipidemie et d'autres etats pathologiques
WO1998051332A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Somatostatine et agonistes de somatostatine pour traiter l'insensibilite a l'insuline et le syndrome x
WO1999056769A2 (fr) * 1998-05-07 1999-11-11 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Inhibition de la proliferation de helicobacter pylori
US6004928A (en) * 1997-05-13 1999-12-21 Biomeasure, Incorporated Method of treating hyperlipidemia
WO2000006185A2 (fr) * 1998-07-30 2000-02-10 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Procedes d'utilisation d'un analogue de somatostatine
US6099862A (en) * 1998-08-31 2000-08-08 Andrx Corporation Oral dosage form for the controlled release of a biguanide and sulfonylurea
US6150333A (en) * 1998-07-30 2000-11-21 Biomeasure, Inc. Methods of using a somatostatin analogue
EP1291022A1 (fr) * 1998-07-30 2003-03-12 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Procédés d'utilisation du lanréotide, un analogue de la somatostatine
WO2005025673A1 (fr) * 2003-09-08 2005-03-24 Franco Folli Therapie multisystemique contre le diabete, le syndrome metabolique et l'obesite comprenant un agent hypoglycemique
US7378488B2 (en) * 2001-03-08 2008-05-27 The Administrators Of The Tulane Educational Fund Somatostatin antagonists
US7572789B2 (en) 2006-01-05 2009-08-11 Essentialis, Inc. Salts of potassium ATP channel openers and uses thereof
EP2208496A1 (fr) 2004-08-25 2010-07-21 Essentialis, Inc. Formulations pharmaceutiques d'activateurs de canaux potassiques atp et leurs utilisations
WO2010093243A1 (fr) * 2009-02-12 2010-08-19 Coöperatieve Mirzorg U.A., Arnhem Utilisation d'une combinaison de diazoxyde et de metformine pour le traitement de l'obésité ou des troubles liés à l'obésité
WO2016038565A1 (fr) * 2014-09-14 2016-03-17 Tel Hashomer Medical Research Infrastructure And Services Ltd. Ligands synthétiques des récepteurs de la somatostatine
US9757384B2 (en) 2005-04-06 2017-09-12 Essentialis, Inc. Methods for treating subjects with Prader-Willi syndrome or Smith-Magenis syndrome
US9765043B2 (en) 2012-02-27 2017-09-19 Essentialls, Inc. Salts of potassium ATP channel openers and uses thereof
US10058557B2 (en) 2014-11-14 2018-08-28 Essentialis, Inc. Methods for treating subjects with prader-willi syndrome or smith-magenis syndrome

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WO1998051330A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Procede et compositions pour traiter l'hyperlipidemie et d'autres etats pathologiques
WO1998051332A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Somatostatine et agonistes de somatostatine pour traiter l'insensibilite a l'insuline et le syndrome x
WO1998051331A1 (fr) * 1997-05-13 1998-11-19 Societe De Conseils De Recherches Et D'applications Scientifiques S.A. (S.C.R.A.S.) Somatostatine et agonistes de somatostatine servant a la reduction du poids corporel
US6004928A (en) * 1997-05-13 1999-12-21 Biomeasure, Incorporated Method of treating hyperlipidemia
US7034003B1 (en) 1997-05-13 2006-04-25 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Somatostatin and somatostatin agonists for decreasing body weight
US7026289B2 (en) 1997-05-13 2006-04-11 Societe De Conseils De Recherches Et D'applications Scientifiques, Sas Method and compositions for treating hyperlipidemia and other conditions
WO1999056769A3 (fr) * 1998-05-07 2000-11-09 Sod Conseils Rech Applic Inhibition de la proliferation de helicobacter pylori
WO1999056769A2 (fr) * 1998-05-07 1999-11-11 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Inhibition de la proliferation de helicobacter pylori
US6150333A (en) * 1998-07-30 2000-11-21 Biomeasure, Inc. Methods of using a somatostatin analogue
EP1291022A1 (fr) * 1998-07-30 2003-03-12 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Procédés d'utilisation du lanréotide, un analogue de la somatostatine
AU770193B2 (en) * 1998-07-30 2004-02-12 Ipsen Pharma S.A.S. Methods of using a somatostatin analogue
WO2000006185A3 (fr) * 1998-07-30 2000-08-03 Biomeasure Inc Procedes d'utilisation d'un analogue de somatostatine
WO2000006185A2 (fr) * 1998-07-30 2000-02-10 Societe De Conseils De Recherches Et D'applications Scientifiques, S.A.S. Procedes d'utilisation d'un analogue de somatostatine
US6099862A (en) * 1998-08-31 2000-08-08 Andrx Corporation Oral dosage form for the controlled release of a biguanide and sulfonylurea
US6284275B1 (en) 1998-08-31 2001-09-04 Andrx Pharmaceuticals, Inc. Controlled release tablet having a unitary core
US7378488B2 (en) * 2001-03-08 2008-05-27 The Administrators Of The Tulane Educational Fund Somatostatin antagonists
US7408024B2 (en) 2001-03-08 2008-08-05 The Administrators Of The Tulane Educational Fund Somatostatin antagonists
WO2005025673A1 (fr) * 2003-09-08 2005-03-24 Franco Folli Therapie multisystemique contre le diabete, le syndrome metabolique et l'obesite comprenant un agent hypoglycemique
EP2208496A1 (fr) 2004-08-25 2010-07-21 Essentialis, Inc. Formulations pharmaceutiques d'activateurs de canaux potassiques atp et leurs utilisations
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US9782416B2 (en) 2004-08-25 2017-10-10 Essentialis, Inc. Pharmaceutical formulations of potassium ATP channel openers and uses thereof
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