WO1998036762A1

WO1998036762A1 - Method of modulating hypothalamic somatostatin release

Info

Publication number: WO1998036762A1
Application number: PCT/US1998/002907
Authority: WO
Inventors: Mark L. Heiman; Libbey S. Craft
Original assignee: Eli Lilly And Company
Priority date: 1997-02-25
Filing date: 1998-02-24
Publication date: 1998-08-27
Also published as: JP2001512481A; EP0991418A1; AU6655998A; CA2282323A1

Abstract

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.

Description

METHOD OF MODULATING HYPOTHALAMIC SOMATOSTATIN RELEASE

BACKGROUND OF THE INVENTION

1. Field of the Invention

2. Description of the Related Art

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.

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. Thus, inhibition of SRIF stimulates GH release. Consequently, 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. Indeed, our data in mice and rats demonstrate this very well. Furthermore, 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 (T₄) and tri-iodothyroxine (T₃). 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 T₃ and T₄ levels such as is observed in general hypothyroidism, thyroiditis, and cretinism. Typically hypothyroidism is associated with increased body mass index, decreased energy expenditure, and decreased body temperature. Leptin therapy is likely to improve such states. We predict that T₃ and T₄ inhibit leptin secretion from the adipocyte. Thus patients treated with thyroid hormone may have reduced leptin levels. Such patients would likely benefit from the combined therapy of leptin and thyroid hormone. SUMMARY OF THE INVENTION

Accordingly, 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.

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. The present invention also thus provides an indirect method for stimulating release of thyroxine (T₄) and t -iodothyroxine (T₃) release from the thyroid gland in mammals in need of such treatment, particularly in cases of general hypothyroidism, thyroiditis, and cretinism.

With the foregoing and other objects, advantages and features of the invention that will become hereinafter apparent, the nature of the invention may be more clearly understood by reference to the following detailed description of the preferred embodiments of the invention and to the appended claims.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

OF THE INVENTION

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.

For purposes of the present invention, as disclosed and claimed herein, the following terms and abbreviations are defined as follows:

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. In double stranded DNA, base pair may refer to a partnership of A with T or C with G. In a DNA/RNA heteroduplex, 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.

FAB-MS - an abbreviation for fast atom bombardment mass spectrometry. 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. For example, 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.

RP-HPLC -- an abbreviation for reversed-phase high performance liquid chromatography.

Transcription - the process whereby information contained in a nucleotide sequence of DNA is transferred to a complementary RNA sequence.

Translation -- the process whereby the genetic information of messenger RNA is used to specify and direct the synthesis of a polypeptide chain.

Tris -- an abbreviation for tris-(hydroxymethyl)aminomethane. Treating - describes the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes the administration of a compound of present invention to prevent the onset of the symptoms or complications, alleviating the symptoms or complications, or eliminating the disease, condition, or disorder. Treating obesity, for example, includes the inhibition of food intake, the inhibition of weight gain, and inducing weight loss in patients in need thereof.

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.

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 (and often with increased body adiposity) 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 (T₄) and tri-iodothyroxine (T₃) release from the thyroid gland, Because increases in TSH result in increases in T₄ and T₃ release from the thyroid gland, The present invention thus provides an indirect method for stimulating release of T₄ and T₃ in mammals in need of such treatment, particularly in cases of general hypothyroidism, thyroiditis, and cretinism.

The inventors have found that administration of leptin receptor ligands, in particular leptin receptor agonists, effectively increases somatostatin release from the hypothalamus. The phrases "receptor ligands", "receptor agonists", and "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). 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., Biochem. Biophys. Res. Com. 209:944-952 (1995). 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

1 5 10 15

Val Pro He Gi n Lys Val Gin Asp Asp Thr Lys Thr Leu He Lys

20 25 30

Thr He Val Thr Arg He Asn Asp He Ser Hi s Thr Xaa Ser Val 35 40 45

Ser Ser Lys Gin Lys Val Thr Gly Leu Asp Phe He Pro Gly Leu

50 55 60

Hi s Pro H e Leu Thr Leu Ser Lys Met Asp Gi n Thr Leu Al a Val

65 70 75 Tyr Gin Gin He Leu Thr Ser Met Pro Ser Arg Asn Val He Gin

80 85 90

He Ser Asn Asp Leu Glu Asn Leu Arg Asp Leu Leu Hi s Val Leu

95 100 105

Ala Phe Ser Lys Ser Cys His Leu Pro Trp Ala Ser Gly Leu Glu 110 115 120

Thr Leu Asp Ser Leu Gly Gly Val Leu Gl u Al a Ser Gly Tyr Ser

125 130 135

Thr Glu Val Val Ala Leu Ser Arg Leu Gin Gly Ser Leu Gin Asp

140 145 Met Leu Trp Gi n Leu Asp Leu Ser Pro Gly Cys or pharmaceutically acceptable salts thereof, wherein:

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;

Asn at position 22 is replaced with Gin or Asp;

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 56 is replaced with Glu; Gin at position 62 is replaced with Glu;

Gin at position 63 is replaced with Glu;

Met at position 68 is replaced with methionine sulfoxide, Leu, lie, Val, Ala, or Gly;

Asn at position 72 is replaced with Gin, Glu, or Asp; Gin at position 75 is replaced with Glu;

Ser at position 77 is replaced with Ala;

Asn at position 78 is replaced with Gin or Asp;

Asn at position 82 is replaced with Gin or Asp;

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,

Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu;

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;

Leu at position 107 is replaced with Pro;

Asp at position 108 is replaced with Glu; Gly at position 111 is replaced with Asp; Gly at position 118 is replaced with Leu;

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.

In addition, 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.

Pharmaceutical salts 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. Examples of 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⁺. In a further embodiment 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. Schwartz (Ed.) (1981); Kohler, G. and Milstein, C, Nature 256: 495-497 (1975) and European Journal of Immunology 6: 511- 519 (1976); Harlow et al.; Koprowski, et al., U.S. Patent 4,172,124; Koprowski et al., U.S. Patent 4,196,265 and Wands, U.S. Patent 4,271 ,145, the teachings of which are herein incorporated by reference.

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).

For therapeutic use in a method of modulating somatostatin and GH levels, 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. Typically, the carrier may be a solid, liquid, or vaporizable carrier, or combinations thereof. In one preferred embodiment, 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.

For example, to prepare formulations suitable for injection, solutions and suspensions are sterilized and are preferably isotonic to blood. In making injectable preparations, 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. In these instances, adequate amounts of 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. For instance, 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.

In general, 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. Typically, 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. To achieve good plasma concentrations, 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. It will be appreciated that 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. Also preferred is the topical route. However, other routes may also be utilized depending on the conditions of the patient and how long-lasting the treatment is. 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.

The above method may be practiced by administration of the compounds by themselves or in a combination with other active ingredients, including therapeutic agents in a pharmaceutical composition. Other 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.

Claims

WHAT IS CLAIMED IS:

1. A method for modulating plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine, said method comprising administering to a mammal in need of such treatment an amount of an leptin receptor ligand effective to alter plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine.

2. The method of claim 1 , wherein said leptin receptor ligand is a leptin receptor agonist.

3. The method of claim 2, wherein said leptin receptor agonist is human leptin.

4. The method of claim 2, wherein said leptin receptor agonist has the amino acid sequence of SEQ ID NO: 1.

5. The method of claim 1 , wherein said leptin receptor ligand is a leptin receptor antagonist.

6. The method of claim 1 , wherein the leptin receptor ligand is administered in an amount of about 0.001 to 100 mg/kg body weight/dose.

7. The method of claim 1 , wherein the leptin receptor ligand is administered orally, intravenously, subcutaneously, topically, transdermally, intramuscularly, or intraperitoneally.

8. The method of claim 1 , wherein the leptin receptor ligand is administered orally.

9. The method of claim 1 , wherein the composition is administered intravenously.

10. The method of claim 1 , wherein the leptin receptor ligand is administered in the form of a pharmaceutical composition of matter which further comprises a pharmaceutically-acceptable carrier.

11. A method for decreasing plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine, said method comprising administering to a mammal in need of such treatment an amount of a specific antibody to a leptin receptor agonist effective to suppress plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine.

12. A method of treating disorders associated with low growth hormone levels such as growth retardation and idiopathic growth hormone- deficiency in children and in adults that were growth hormone deficient as children or that become growth hormone-deficient after puberty, Turner's syndrome, and/or aging, comprising administering a leptin receptor agonist in an amount effective to increase plasma growth hormone levels.

13. A method of treating disorders associated with hypersecretion of growth hormone, such as acromegaly, comprising administering a leptin receptor antagonist in an amount effective to decrease plasma growth hormone levels.

14. A method of treating disorders associated with hypersecretion of growth hormone, such as acromegaly, comprising administering specific anti-leptin antibodies in an amount effective to increase plasma glucocprticoid levels.

15. A method of treating general hypothyroidism, thyroiditis, and cretinism, comprising administering a leptin receptor agonist in an amount sufficient to stimulate increases in thyroxine and tri-iodothyroxine release from the thyroid gland.

16. A pharmaceutical composition of matter for modulating plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine, comprising a leptin receptor ligand in an amount effective to alter plasma levels of somatostatin, growth hormone, thyroxine, and tri-iodothyroxine, and a pharmaceutically acceptable carrier therefor.

17. The method of claim 16, wherein said leptin receptor ligand is a leptin receptor agonist.

18. The method of claim 16, wherein said leptin receptor ligand is a leptin receptor antagonist.