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WO1998036762A1 - Procede de stimulation de la liberation de la somatostatine hypothalamique - Google Patents

Procede de stimulation de la liberation de la somatostatine hypothalamique Download PDF

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Publication number
WO1998036762A1
WO1998036762A1 PCT/US1998/002907 US9802907W WO9836762A1 WO 1998036762 A1 WO1998036762 A1 WO 1998036762A1 US 9802907 W US9802907 W US 9802907W WO 9836762 A1 WO9836762 A1 WO 9836762A1
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WO
WIPO (PCT)
Prior art keywords
leptin receptor
growth hormone
leptin
receptor ligand
iodothyroxine
Prior art date
Application number
PCT/US1998/002907
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English (en)
Inventor
Mark L. Heiman
Libbey S. Craft
Original Assignee
Eli Lilly And Company
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Eli Lilly And Company filed Critical Eli Lilly And Company
Priority to JP53674998A priority Critical patent/JP2001512481A/ja
Priority to AU66559/98A priority patent/AU6655998A/en
Priority to CA002282323A priority patent/CA2282323A1/fr
Priority to EP98908554A priority patent/EP0991418A1/fr
Publication of WO1998036762A1 publication Critical patent/WO1998036762A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • A61K38/16Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22Hormones
    • A61K38/2264Obesity-gene products, e.g. leptin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/02Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/38Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/44Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids

Definitions

  • This invention relates generally to a method for modulating hypothalamic somatostatin release in a mammal in need of such treatment by administration of a therapeutically effective amount of a leptin receptor ligand.
  • the present invention also relates to a method of modulating plasma levels of growth hormone, thyroxine, and tri-iodothyroxine by administration of a therapeutically effective amount of a leptin receptor ligand, or specific antibodies to leptins.
  • the present inventors were the first to demonstrate that leptin inhibits neuropeptide Y (NPY) synthesis and release by the hypothalamus. These data have since been confirmed by others (1). More recently, the present inventors have observed that leptin inhibits corticotropin-releasing hormone (CRH) from the hypothalamus. We now extend this neuroendocrinology of leptin to include inhibition of somatostatin (SRIF) release.
  • NPY neuropeptide Y
  • CSH corticotropin-releasing hormone
  • SRIF is a hypophysiotropic peptide produced by neurons in the periventricular nucleus of the hypothalamus.
  • the peptide is well- documented to inhibit release of growth hormone (GH) from the pituitary gland.
  • GH growth hormone
  • leptin can be used to stimulate plasma GH in pathophysiologic states of GH-insufficiency or GH-deficiency.
  • Plasma GH levels are suppressed in obesity. Treatment of obesity by dramatic restriction of diet or fasting does not appropriately stimulate GH levels, and patients that lose weight often lose muscle mass with adipose mass. Since leptin inhibits SRIF release, it can be used as hormonal therapy for obesity and maintain lean body mass.
  • mice and rats demonstrate this very well.
  • the adipocyte contains GH receptors that mediate lipolytic activity. GH also decreases leptin secretion from the adipocyte and thus completes a neuroendocrine axis.
  • GH-deficient states typically associated with increased adiposity such as observed in a small percentage of children with growth retardation and idiopathic GH-deficiency, adults that were GH deficient as children or that become GH deficient after puberty, Turner's syndrome and aging may all be treated by leptin. Since GH therapy appears to inhibit plasma leptin levels, GH therapy may need to be combined with leptin.
  • SRIF also inhibits thyroid-stimulating hormone (TSH) release by the pituitary gland. Since leptin inhibits SRIF, that leptin can be used to stimulate TSH release which, in turn, stimulates release of thyroxine (T 4 ) and tri-iodothyroxine (T 3 ). Both thyroid hormones have a profound effect to stimulating metabolic rate and thus energy expenditure. In human, the hypothalamic-pituitary-thyroid axis is not only important for maintenance of metabolism but also temperature regulation. Our data suggest that leptin may be useful as a therapy to stimulate T 3 and T 4 levels such as is observed in general hypothyroidism, thyroiditis, and cretinism.
  • TSH thyroid-stimulating hormone
  • hypothyroidism is associated with increased body mass index, decreased energy expenditure, and decreased body temperature. Leptin therapy is likely to improve such states.
  • T 3 and T 4 inhibit leptin secretion from the adipocyte.
  • patients treated with thyroid hormone may have reduced leptin levels. Such patients would likely benefit from the combined therapy of leptin and thyroid hormone.
  • a major object of the present invention is to provide a method of modulating somatostatin (SRIF) release by the hypothalamus by administering leptin receptor ligands to a mammal in need of such treatment.
  • SRIF somatostatin
  • the present invention also provides a method of increasing plasma GH in pathophysiologic states of GH-insufficiency or GH-deficiency comprising administering leptin receptor ligands to a mammal in need of such treatment. More specifically, the present invention provides methods of treating GH-deficient states typically associated with increased adiposity such as observed in a small percentage of children with growth retardation and idiopathic GH-deficiency, in adults that were GH deficient as children or that become GH deficient after puberty, Turner's syndrome, and/or aging comprising administering leptin receptor ligands in an amount sufficient to increase plasma GH levels.
  • the present invention also provides a method of decreasing GH release in a mammal in need of such treatment comprising administering leptin receptor antagonists, or specific antibodies to leptins, to a mammal in need of such treatment.
  • the present invention also provides a method of stimulating thyroid- stimulating hormone (TSH) release by the pituitary gland in a mammal in need of such treatment, comprising administering a leptin receptor agonist in an amount sufficient to stimulate TSH release.
  • TSH thyroid- stimulating hormone
  • the present invention also thus provides an indirect method for stimulating release of thyroxine (T 4 ) and t -iodothyroxine (T 3 ) release from the thyroid gland in mammals in need of such treatment, particularly in cases of general hypothyroidism, thyroiditis, and cretinism.
  • This invention arose from a desire of the inventors to improve on previously available methods of modulating somatostatin levels. More specifically, the inventors sought to provide a safe, effective treatment for growth hormone deficiency, in particular a treatment which would increase plasma growth hormone levels in a mammal in need of such treatment.
  • Base pair (bp) - refers to DNA or RNA.
  • the abbreviations A,C,G, and T correspond to the 5'-monophosphate forms of the nucleotides (deoxy)adenine, (deoxy)cytidine, (deoxy)guanine, and (deoxy)thymine, respectively, when they occur in DNA molecules.
  • the abbreviations U,C,G, and T correspond to the 5'-monophosphate forms of the nucleosides uracil, cytidine, guanine, and thymine, respectively when they occur in RNA molecules.
  • base pair may refer to a partnership of A with T or C with G.
  • base pair may refer to a partnership of T with U or C with G.
  • Chelating Peptide An amino acid sequence capable of complexing with a multivalent metal ion.
  • DNA Deoxyribonucleic acid.
  • EDTA - an abbreviation for ethylenediamine tetraacetic acid.
  • ED50 - an abbreviation for half-maximal value.
  • Hypothalamic-Pituitary-Adrenal-Adipose Axis HPAAA: A physiological regulatory system wherein each of the named elements (the hypothalamus, the pituitary gland, the adrenal glands, and adipose tissue) release chemicals that regulate the activity of the others.
  • HPAAA Hypothalamic-Pituitary-Adrenal-Adipose Axis
  • CRH released by the hypothalamus stimulates pituitary secretion of ACTH, that in turn stimulates adrenal secretion of glucocorticoids, which in turn modulates adipose tissue leptin release, that finally acts back on the hypothalamus.
  • Immunoreactive Protein(s) - a term used to collectively describe antibodies, fragments of antibodies capable of binding antigens of a similar nature as the parent antibody molecule from which they are derived, and single chain polypeptide binding molecules as described in PCT Application No. PCT/US 87/02208, International Publication No. WO 88/01649. mRNA - messenger RNA.
  • MWCO an abbreviation for molecular weight cut-off. Modulating -- stimulating, potentiating, or inhibiting the activity of a receptor or system.
  • Plasmid an extrachromosomal self-replicating genetic element.
  • PMSF an abbreviation for phenylmethylsulfonyl fluoride.
  • Reading frame the nucleotide sequence from which translation occurs "read” in triplets by the translational apparatus of tRNA, ribosomes and associated factors, each triplet corresponding to a particular amino acid. Because each triplet is distinct and of the same length, the coding sequence must be a multiple of three. A base pair insertion or deletion (termed a frameshift mutation) may result in two different proteins being coded for by the same DNA segment. To insure against this, the triplet codons corresponding to the desired polypeptide must be aligned in multiples of three from the initiation codon, i.e. the correct "reading frame" must be maintained. In the creation of fusion proteins containing a chelating peptide, the reading frame of the DNA sequence encoding the structural protein must be maintained in the DNA sequence encoding the chelating peptide.
  • Receptor agonist any compound that binds to a receptor and triggers the action of the receptor (usually an intracellular signalling event or, in the case of receptors that form transmembrane channel, the opening or closing of the channel).
  • Receptor antagonist any compound that binds to a receptor and blocks the action of the receptor (usually by out-competing the endogenous agonist for binding sites on the receptor).
  • Receptor ligand any compound that binds to a receptor.
  • Recombinant DNA Cloning Vector any autonomously replicating agent including, but not limited to, plasmids and phages, comprising a DNA molecule to which one or more additional DNA segments can or have been added.
  • Recombinant DNA Expression Vector any recombinant DNA cloning vector in which a promoter has been incorporated.
  • Replicon - A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector.
  • RNA - ribonucleic acid A DNA sequence that controls and allows for autonomous replication of a plasmid or other vector.
  • Vector - a replicon used for the transformation of cells in gene manipulation bearing polynucieotide sequences corresponding to appropriate protein molecules which, when combined with appropriate control sequences, confer specific properties on the host cell to be transformed.
  • Plasmids, viruses, and bacteriophage are suitable vectors, since they are replicons in their own right.
  • Artificial vectors are constructed by cutting and joining DNA molecules from different sources using restriction enzymes and ligases. vectors include Recombinant DNA cloning vectors and Recombinant DNA expression vectors.
  • X-gal - an abbreviation for 5-bromo-4-chloro-3-idolyl beta-D- galactoside.
  • the present invention provides a method of modulating somatostatin (SRIF) release by the hypothalamus by administering leptin receptor ligands to a mammal in need of such treatment.
  • SRIF somatostatin
  • the present invention also provides a method of increasing plasma GH in pathophysiologic states of GH-insufficiency or GH-deficiency comprising administering leptin receptor agonists to a mammal in need of such treatment.
  • Disorders associated with low growth hormone levels include growth retardation and idiopathic GH-deficiency, in children and in adults that were GH deficient as children or that become GH deficient after puberty, Turner's syndrome, and/or aging.
  • the present invention also provides a method of decreasing GH release in a mammal in need of such treatment comprising administering leptin receptor antagonists, or specific antibodies to leptins, to a mammal in need of such treatment.
  • Disorders associated with hyper-release of GH include acromegaly.
  • the present invention also provides a method of stimulating thyroid- stimulating hormone (TSH) release by the pituitary gland in a mammal in need of such treatment , comprising administering a leptin receptor agonist in an amount sufficient to stimulate TSH release. Because increases in TSH result in increases in thyroxine (T 4 ) and tri-iodothyroxine (T 3 ) release from the thyroid gland, Because increases in TSH result in increases in T 4 and T 3 release from the thyroid gland, The present invention thus provides an indirect method for stimulating release of T 4 and T 3 in mammals in need of such treatment, particularly in cases of general hypothyroidism, thyroiditis, and cretinism.
  • TSH thyroid- stimulating hormone
  • leptin receptor ligands in particular leptin receptor agonists
  • receptor ligands in particular leptin receptor agonists
  • receptor antagonists used herein are understood to refer to pharmacologically active compounds, and to salts thereof.
  • Preferred leptin receptor agonists for use in the present invention include endogenous leptin (i.e., endogenous OB protein - the protein produced from the obesity gene following transcription and translation and deletion of introns, translation to a protein and processing to the mature protein with secretory signal peptide removed, e.g., from the N-terminal valine-proline to the C-terminal cysteine of the mature protein).
  • endogenous leptin i.e., endogenous OB protein - the protein produced from the obesity gene following transcription and translation and deletion of introns, translation to a protein and processing to the mature protein with secretory signal peptide removed, e.g., from the N-terminal valine-proline to the C-terminal cysteine of the mature protein.
  • the mouse OB protein and human OB protein are published in Zhang et al., Nature 372:425-432 (1994).
  • the rat OB protein is published in Murakami et al.,
  • the porcine and bovine OB genes and proteins are disclosed in EP 0 743 321 , the contents of which are incorporated by reference.
  • Various primate OB genes and proteins are disclosed in U.S. Application Serial No.08/710,483, the contents of which are incorporated by reference.
  • Also preferred for use in the present invention are leptin analogs, preferably leptin analogs having one or more amino acid substitution, more preferably less than five and most preferably less than three substitutions.
  • Particularly preferred leptin analogs for use in the present invention include proteins disclosed by Basinski et al., in WO 96/23515 and WO 96/23517 (the contents of which are incorporated by reference), of the Formula (l): SEQ ID NO: 1
  • Xaa at position 28 is Gin or absent; said protein having at least one of the following substitutions: Gln at position 4 is replaced with Glu;
  • Gin at position 7 is replaced with Glu
  • Thr at position 27 is replaced with Ala; Xaa at position 28 is replaced with Glu;
  • Gin at position 34 is replaced with Glu
  • Met at position 54 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly;
  • Gin at position 63 is replaced with Glu
  • Met at position 68 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly;
  • Gin at position 72 is replaced with Gin, Glu, or Asp; Gin at position 75 is replaced with Glu;
  • His at position 97 is replaced with Gin, Asn, Ala, Gly, Ser, or Pro; Trp at position 100 is replaced with Ala, Glu, Asp, Asn, Met, lie,
  • Ala at position 101 is replaced with Ser, Asn, Gly, His, Pro, Thr, or Val;
  • Ser at position 102 is replaced with Arg; Gly at position 103 is replaced with Ala;
  • Glu at position 105 is replaced with Gin
  • Thr at position 106 is replaced with Lys or Ser;
  • Gin at position 130 is replaced with Glu
  • Gin at position 134 is replaced with Glu
  • Met at position 136 is replaced with methionine sulfoxide, Leu, He, Val, Ala, or Gly;
  • Trp at position 138 is replaced with Ala, Glu, Asp, Asn, Met, He, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu; or
  • Gin at position 139 is replaced with Glu.
  • the compounds of the present invention are optionally substituted with a functional group.
  • Any art-recognized functional group which does not eliminate or significantly reduce the compound's ability to bind to leptin receptors are contemplated, including, but not limited to, ester, amide, acid, amine, alcohol, ether, thioether, etc.
  • Solvates e.g., hydrates of the compounds useful in the methods of the present invention, are also included within the scope of the present invention. Methods of soivation to produce such solvates are generally known in the art.
  • compositions of the leptin receptor agonists and antagonists suitable for administration by a variety of routes are known in the art and need not be described herein in detail.
  • pharmaceutically acceptable salts of the compounds and derivatives thereof according to the invention include base salts, e.g., derived from an appropriate base.
  • Pharmaceutically acceptable salts of an acid group or an amino group include, but are not limited to, salts of organic carboxylic acids such as acetic, lactic, tartaric, malic, isothionic, and lactobionic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-tolylsulfonic acids, and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids.
  • Pharmaceutically-acceptable salts of a compound with a hydroxy group include, but are not limited to, the anion of the compound in combination with a suitable cation such as Na + .
  • the present invention comprises a method for decreasing plasma somatostatin and GH levels by administration of antibodies to endogenous leptin receptor agonists to a mammal in need of such treatment.
  • Such antibodies may be monoclonal or polyclonal antibodies to leptin receptor agonists, or to antigenic parts thereof. Both polyclonal and monoclonal antibodies to leptin receptor agonists are obtainable by immunization of an animal with purified leptin receptor agonists, purified recombinant leptin receptor agonists, fragments of these proteins, or purified fusion proteins of leptin receptor agonists, with another protein. In the case of monoclonal antibodies, partially purified proteins or fragments may serve as immunogens. The methods of obtaining both types of antibodies are well known in the art with excellent protocols for antibody production being found in Harlow et al. (1988) Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, 726 pp.
  • Polyclonal sera are relatively easily prepared by injection of a suitable laboratory animal with an effective amount of purified leptin receptor agonists, or parts thereof, collecting serum from the animal, and isolating specific sera by any of the known immunoadsorbent techniques.
  • Monoclonal antibodies are particularly useful because they can be produced in large quantities and with a high degree of homogeneity.
  • Hybridoma cell lines which produce monoclonal antibodies are prepared by fusing an immortal cell line with lymphocytes sensitized against the immunogenic preparation and is done by techniques which are well known to those who are skilled in the art. (See, for example, Douillard, I.Y. and Hoffman, T., "Basic Facts About Hybridomas", in Compendium of Immunology, Vol. II, L.
  • a still further part of this invention is a pharmaceutical composition of matter for increasing or decreasing plasma somatostatin and GH levels that comprises at least one of the leptin receptor agonists or antagonists described above, mixtures thereof, and/or pharmaceutical salts thereof, and a pharmaceutically-acceptable carrier therefor.
  • Such compositions are prepared in accordance with accepted pharmaceutical procedures, for example, as described in Remington's Pharmaceutical Sciences, seventeenth edition, ed. Alfonso R. Gennaro, Mack Publishing Company, Easton, PA (1985).
  • a leptin receptor agonist or antagonist, or its salt can be conveniently administered in the form of a pharmaceutical composition containing one or more leptin receptor agonists or antagonists, or salts thereof, and a pharmaceutically acceptable carrier therefor.
  • Suitable carriers are well known in the art and vary with the desired form and mode of administration of the pharmaceutical composition. For example, they may include diluents or excipients such as fillers, binders, wetting agents, disintegrators, surface-active agents, lubricants, and the like.
  • the carrier may be a solid, liquid, or vaporizable carrier, or combinations thereof.
  • the composition is a therapeutic composition and the carrier is a pharmaceutically acceptable carrier.
  • a compound for use in the present invention, or its salt, may be formulated together with the carrier into any desired unit dosage form.
  • Typical unit dosage forms include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories; injectable solutions and suspensions are particularly preferred.
  • Each carrier must be “acceptable” in the sense of being compatible with the other ingredients in the formulation and not injurious to the patient.
  • the carrier must be biologically acceptable and inert, i.e., it must permit the cell to conduct its metabolic reactions so that the compound of this invention may effect its inhibitory activity.
  • Formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, and transdermal) administration, with topical ointment formulations, and formulations appropriate for oral administration, being preferred.
  • solutions and suspensions are sterilized and are preferably isotonic to blood.
  • carriers which are commonly used in this field can also be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitate esters.
  • isotonicity adjusters such as sodium chloride, glucose or glycerin can be added to make the preparations isotonic.
  • the aqueous sterile injection solutions may further contain anti-oxidants, buffers, bacteriostats, and like additions acceptable for parenteral formulations.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which may encompass one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product. Various unit dose and multidose containers, e.g., sealed ampules and vials, may be used, as is well known in the art. In addition to the ingredients particularly mentioned above, the formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation.
  • a compound for use in the present invention may be present in the composition in an broad proportion to the carrier.
  • the compound may be present in the amount of 0.01 to 99.9 wt%, and more preferably in about 0.1 to 99 wt%. Still more preferably, the compound may be present in an amount of about 1 to 70 wt% of the composition.
  • the dosage of the leptin receptor agonists or antagonists, pharmaceutically acceptable salts thereof, or mixtures thereof, administered to a patient according to the present invention will vary depending on several factors, including, but not limited to, the age, weight, and species of the patient, the general health of the patient, the severity of the symptoms, whether the composition is being administered alone or in combination with other therapeutic agents, the incidence of side effects and the like.
  • a dose suitable for application in modulating GH and somatostatin levels is about 0.001 to 100 mg/kg body weight/dose, preferably about 0.01 to 60 mg/kg body weight/dose, and still more preferably about 0.1 to 40 mg/kg body weight/dose per day.
  • the desired dose may be administered as 1 to 6 or more subdoses administered at appropriate intervals throughout the day.
  • the compounds may be administered repeatedly over a period of months or years, or it may be slowly and constantly infused to the patient. Higher and lower doses may also be administered.
  • the daily dose may be adjusted taking into account, for example, the above-identified variety of parameters.
  • the present compositions may be administered in an amount of about 0.001 to 100 mg/kg body weight/day. However, other amounts may also be administered.
  • the active compounds may be administered, for instance, by intravenous injection of an approximate 0.1 to 1% solution of the active ingredient, optionally in saline, or orally administered as a bolus.
  • the active ingredient may be administered for therapy by any suitable routes, including topical, oral, rectal, nasal, vaginal and parenteral (including intraperitoneal, subcutaneous, intramuscular, intravenous, intradermal, and transdermal) routes.
  • the preferred route will vary with the condition and age of the patient, the nature of the disorder and the chosen active ingredient including other therapeutic agents.
  • Preferred is the oral route.
  • topical route is preferred.
  • other routes may also be utilized depending on the conditions of the patient and how long-lasting the treatment is.
  • the active ingredient While it is possible for the active ingredient to be administered alone, it is preferably present as a pharmaceutical formulation.
  • the formulations of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers thereof and optionally other therapeutic agents.
  • therapeutic agents suitable for use herein are any compatible drugs that are effective by the same or other mechanisms for the intended purpose, or drugs that are complementary to those of the present agents. These include agents that are effective for the treatment of obesity or hypothyroidism and/or associated conditions in humans.
  • the compounds utilized in combination therapy may be administered simultaneously, in either separate or combined formulations, or at different times than the present compounds, e.g., sequentially, such that a combined effect is achieved.
  • the amounts and regime of administration will be adjusted by the practitioner, by preferably initially lowering their standard doses and then titrating the results obtained.
  • the therapeutic method of the invention may be used in conjunction with other therapies as determined by the practitioner. While the invention has been described and illustrated herein by references to various specific material, procedures and examples, it is understood that the invention is not restricted to the particular material, combinations of material, and procedures selected for that purpose. Numerous variations of such details can be implied and will be appreciated by those skilled in the art.

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Abstract

La présente invention concerne principalement un procédé permettant de stimuler la libération de la somatostatine par l'hypothalamus d'un mammifère nécessitant un tel traitement. Le procédé consiste en l'occurrence en l'administration d'une quantité, suffisante d'un point de vue thérapeutique, d'un ligand du récepteur de la leptine. L'invention concerne également un procédé de modulation des niveaux d'hormone de croissance, de thyroxine et de tri-iodothyroxine et consistant en l'administration d'une quantité, suffisante d'un point de vue thérapeutique, d'un ligand du récepteur de la leptine ou d'anticorps spécifiques des leptines.
PCT/US1998/002907 1997-02-25 1998-02-24 Procede de stimulation de la liberation de la somatostatine hypothalamique WO1998036762A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP53674998A JP2001512481A (ja) 1997-02-25 1998-02-24 視床下部ソマトスタチン放出の調節方法
AU66559/98A AU6655998A (en) 1997-02-25 1998-02-24 Method of modulating hypothalamic somatostatin release
CA002282323A CA2282323A1 (fr) 1997-02-25 1998-02-24 Procede de stimulation de la liberation de la somatostatine hypothalamique
EP98908554A EP0991418A1 (fr) 1997-02-25 1998-02-24 Procede de stimulation de la liberation de la somatostatine hypothalamique

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US80604697A 1997-02-25 1997-02-25
US08/806,046 1997-02-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1854475A4 (fr) * 2005-02-23 2012-04-04 Univ Illes Balears Utilisation de la leptine dans la prevention d'une surcharge ponderale et composition contenant de la leptine

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023815A1 (fr) * 1995-01-31 1996-08-08 Eli Lilly And Company Anticorps contre les produits du gene ob

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996023815A1 (fr) * 1995-01-31 1996-08-08 Eli Lilly And Company Anticorps contre les produits du gene ob

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1854475A4 (fr) * 2005-02-23 2012-04-04 Univ Illes Balears Utilisation de la leptine dans la prevention d'une surcharge ponderale et composition contenant de la leptine

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EP0991418A1 (fr) 2000-04-12
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AU6655998A (en) 1998-09-09

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