EP1128840A1 - Verhinderung eines muskelmasseverlust mit liganden des leptinrezeptors - Google Patents

Verhinderung eines muskelmasseverlust mit liganden des leptinrezeptors

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Publication number
EP1128840A1
EP1128840A1 EP99955171A EP99955171A EP1128840A1 EP 1128840 A1 EP1128840 A1 EP 1128840A1 EP 99955171 A EP99955171 A EP 99955171A EP 99955171 A EP99955171 A EP 99955171A EP 1128840 A1 EP1128840 A1 EP 1128840A1
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EP
European Patent Office
Prior art keywords
leptin
leptin receptor
receptor ligand
administered
receptor
Prior art date
Legal status (The legal status 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 status listed.)
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EP99955171A
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English (en)
French (fr)
Inventor
Mark L. Heiman
Frank C. Tinsley
Jose F. Caro
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Eli Lilly and Co
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Eli Lilly and Co
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Publication of EP1128840A1 publication Critical patent/EP1128840A1/de
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    • 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
    • A61K38/2264—Obesity-gene products, e.g. leptin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism

Definitions

  • This invention relates generally to methods for preventing the loss of lean tissue or muscle mass during catabolic states associated with improper nutrition, and methods for increasing lean tissue growth, in a mammal in need of such treatment by administration of a therapeutically effective amount of a leptin receptor agonist.
  • adipose tissue performs important biological functions beyond storage of fat.
  • adipose tissue functions very much like any other endocrine tissue, providing a change in circulating leptin that is perceived by the brain as a signal of lipid storage level.
  • leptin is secreted from adipocytes (45) into blood of rodents (33) and human (11 , 33) was presented.
  • the major target for this hormonal message appears to be the hypothalamus.
  • a mutation in the Lepr 13 locus results in a spliced transcript that is proposed to be incapable of signal transduction, leads to leptin resistance, and is likely the cause of severe obesity and diabetes reported in Lep ⁇ /Lepr 13 mice (8, 20, 57).
  • the wild-type leptin receptor gene has a long intracellular domain that is thought to be crucial for intracellular signal transduction (57). This receptor closely resembles class I cytokine receptors and is only located in hypothalamus.
  • Spliced variant isoforms of the Lepr are also located in many tissues including hypothalamus, choroid plexus, heart, lung, liver, skeletal muscle, and kidney. Functions for these variants may involve transport of leptin from blood to its target cells (2, 22).
  • leptin fulfills Starling's definition of a hormone. It is carried from adipose where it is secreted to the hypothalamus by means of the circulatory system and the continually recurring storage and dissipation of lipid determines its production and secretion.
  • hypothalamus is the principal leptin target
  • Leptin's message is perceived by hypothalamic tissue that expresses full-length in the arcuate, ventromedial, dorsomedial, and lateral hypothalamic nuclei (17). Only this full-length receptor can transduce the leptin hormonal signal to a neuronal directive (57). In the arcuate nucleus, leptin reduces the excitatory input to neuropeptide-Y (NPY) neurons and produces inhibitory postsynaptic effects (21 ) that rapidly decreases NPY release (47). Long term leptin signaling results in decreased NPY mRNA expression (42, 47).
  • NPY neurons of the arcuate nucleus As a major center for regulating fuel homeostasis and its associated adaptive endocrinology. These NPY neurons project to other areas of the hypothalamus that regulate feeding behavior and coordinate neuroendocrine secretion (9). Careful mapping of NPY stimulated feeding has been reported (46). Fasting and starvation are powerful stimuli while refeeding is inhibitory to these neurons and their synapses. In concert, hormones responsible for metabolic homeostasis are regulated by NPYergic transmission.
  • NPY neurons Activation of NPY neurons is associated with increased insulin secretion (59), activation of the hypothalamic-pituitary-adrenal axis (55), and inhibition of the thyrotropin releasing hormone-thyroid axis (24) and the hypothalamic-growth hormone axis.
  • both episodic basal and cyclic release of luteinizing hormone-releasing hormone (LHRH) are stimulated by NPY, rendering appropriate output from these neurons essential for fertility (27, 28).
  • hypothalamus While leptin signaling in the arcuate nucleus is inhibitory, neurons in the ventromedial, dorsomedial, and ventral premammillary hypothalamic nuclei appear to be activated by leptin (16, 53). These neurons may release satiety neuropeptides such as cholecystokinin and cortiocotropin-releasing hormone (CRH) that are also important hypothalamic components of the sympathetic nervous system (19, 40) that participate in regulation of body temperature, resting energy expenditure gastrointestinal motility, and insulin secretion.
  • CSH cortiocotropin-releasing hormone
  • the hypothalamus is an important central processing center that integrates neuroendocrine circuits and it depends on leptin afferent information to extend some or all neuroendocrine feedback loops, especially those that are dependent and differentially regulated by fuel reserve level.
  • hypothalamic-pituitary-adrenal-adipose axis HPAAA
  • CRH neurons comprise much of the complex hypothalamic paraventricular nucleus (PVN) that is divided into neurons that project to the median eminence (30, 56) and neurons that give rise to descending efferent autonomic transmission (41 ).
  • PVN hypothalamic paraventricular nucleus
  • induction of Fos protein after acute intravenous leptin administration was detected in only these latter autonomic regions of the PVN (16).
  • Fos immunoactivity was not noticeably altered in the medial subneurons that contain CRH, project to the median eminence, and participate in regulation of the HPAA.
  • leptin inhibits hypoglycemia mediated CRH release in vitro and stress stimulated HPAA in vivo (26).
  • the etiology of obesity observed in Lep ob / Lep ob mice involves failure to produce mature leptin (60) and replacement of leptin by exogenous administration to Lep ob /Lep ob mice corrects the hypercorticism (47). Rapid frequent blood sampling of 6 healthy men permitted the measurement of leptin, ACTH and cortisol for 24 h (32). These data clearly demonstrate that plasma leptin concentrations are inversely correlated to both plasma ACTH and plasma cortisol levels, supporting an inhibitory role for leptin on the HPAA. Prolonged fasting, that activates the HPAA, is accompanied by decreased endogenous leptin secretion.
  • the activated HPAA during fasting is attenuated by administration of exogenous leptin (1 ).
  • exogenous leptin 1
  • elevated plasma ACTH and corticosterone levels resulting from restraint stress are blocked by administration of exogenous leptin (26).
  • Leptin actions at the pituitary level of the HPAA are unclear.
  • Full length leptin receptor mRNA has been detected in the adenohypophysis of mice (37) and sheep (15).
  • Mouse pituitary slices in perifusion release ACTH (1.5 - 2 fold) acutely when incubated with leptin (37).
  • leptin receptors Although there is no demonstration of leptin receptors in the adrenal gland, leptin has been reported to inhibit cortisol release from primary cultured bovine adrenal cortex cells (3).
  • Cortisol stimulates leptin secretion (14, 45, 54) and this finding permits insertion of leptin in feedback regulation of the HPAA (Fig. 1 ).
  • Physiological states of low fuel supply such as fasting are characterized by low circulating leptin levels.
  • plasma ACTH and glucocorticoid levels are stimulated by increased CRH release into the median eminence. Whether decreased leptin levels release inhibition of CRH release directly or indirectly by releasing inhibition of NPY stimulated CRH release (51 , 55) is not known.
  • elevated glucocorticoid stimulates leptin secretion to complete this negative feedback axis.
  • hypothalamic-pituitary-adrenal axis is intact with negative feedback exerted by glucocorticoid at both the hypothalamus and pituitary, but nevertheless remains activated.
  • glucocorticoid levels result in over- expression of NPY and thus obesity that is corrected by leptin replacement.
  • GH Growth hormone
  • GH secretion of GH is regulated by complex interaction of neural and hormonal feedback systems that result in a striking pulsatile pattern. Extensive evidence indicates that this episodic pattern of GH release is produced by interchange between at least two hypothalamic hormones; a GH releasing hormone (GHRH) and an inhibitory hormone, somatostatin (SRIF) (25, 49). Such inhibition may be direct or it may be a consequence of leptin inhibition of NPY release (47) because NPY neurons stimulate release of SRIF (63).
  • GHRH GH releasing hormone
  • SRIF somatostatin
  • IGF-1 insulinlike growth factor-l
  • IGF-I insulinlike growth factor-1
  • anabolic actions of GH may be mediated through IGF-I (68). It is still debatable if GH-mediated production of IGF-I has local autocrine and paracrine physiology or whether the peptide is secreted into the circulation and functions as a hormone. In fact, significant local stimulation of IGF-I may leak into the general circulation to function as a hormone. Although IGF-I is produced by most organs, the liver is the major source of the circulating peptide (64). Circulating IGF-I feeds back to inhibit GH release at both the pituitary (69) and hypothalamus (61 ,75) to complete this neuroendocrine feedback loop.
  • IGF-l also appears to inhibit leptin gene expression by rat adipose tissue (62,74). Such decreased circulating leptin would release its inhibition of SRIF release and therefore augment IGF-I inhibition of GH secretion.
  • hypothalamic-GH-IGF-l axis should be extended to include leptin (Fig. 2). Indeed, GH-deficient adults present depressed circulating IGF-l levels and elevated plasma leptin concentrations that are corrected by GH replacement therapy (67,66).
  • Recent clinical observations and experimental animal data clearly indicate that regulation of this neuroendocrine axis is substantially impacted by nutrition (71 ).
  • IGF-I levels do not change during overnutrition (73).
  • most phenotypes of human obesity are associated with reduced GH levels and either decreased or normal IGF-I levels (71 ).
  • the glucocorticoid and GH axes be extended to include leptin feedback.
  • Recent studies by Ahima and colleagues (1 ) also imply that leptin feedback be included in regulation of the thyroid and reproduction axes. During states of scarce fuel supply, leptin levels fall yielding a signal for energy replenishment such as increased feeding and augmented glucocorticoid secretion.
  • a major object of the present invention is to provide a method of preventing the loss of lean tissue mass associated with improper nutrition or fasting.
  • Leptin used as an adjunct in weight loss programs would not only aid the weight loss itself but would prevent the associated loss of muscle.
  • the use of leptin and leptin receptor ligands may also result in an increase in lean tissue mass, which represents an opportunity for therapy during catabolic states such as cachexia resulting from illnesses such as anorexia and malnutrition. Methods of increasing lean tissue growth would also be useful in the fields of veterinary science and animal husbandry in benefitting the health and quality of livestock.
  • This invention discloses the utility of leptin, leptin mimetics, or novel leptin analogs in preventing the loss of or increasing lean tissue mass in either obese or lean subjects.
  • leptin, leptin mimetics, or novel leptin analogs may be used to increase lean body mass.
  • Base pair (bp) -- refers to DNA or RNA.
  • the abbreviations A,C,G, and T correspond to the ⁇ '-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.
  • 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 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.
  • 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 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.
  • MWCO an abbreviation for molecular weight cut-off.
  • 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.
  • the preferred receptor ligands of the present invention include leptin, leptin mimetics and leptin analogs. Chemically modified leptin, particularly mono- and poly- pegylated leptin may also be used. The structure and advantages of such modified compounds are known in the art, as evidenced by European patent applications EP 0741187 and EP 0822199, herein incorporated by reference.
  • 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 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.
  • 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 leptin receptor ligand of the 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 polynucleotide 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.
  • Leptin receptor agonists may be used to preserve or increase lean body or tissue mass.
  • the inventors have found that administration of leptin receptor ligands, in particular leptin receptor agonists, effectively may be used to prevent against the loss of lean tissue mass associated with improper nutrition. Specifically, it has been found that administration of leptin to either normal rats fed a low fat diet or rats fed a diet rich in fat for 2- 4 weeks results in the loss of significant quantities of adipose tissue but the preservation of lean tissue mass.
  • Leptin administration initially resulted in anorexia during the first two weeks of treatment. However, decreased food consumption waned with further treatment and the animals resumed eating similar quantities of food as did the ad libitum control rats. None-the-less, leptin treatment continued to result in fat loss and defend against lean tissue loss.
  • leptin or OB protein administered to a leptin-sufficient animal or human would not produce starvation and would actually prevent lean tissue (muscle) loss during catabolic states such as cachexia, anorexia and malnutrition. Indeed, since such patients are usually hospitalized with intravenous therapy, leptin or leptin receptor agonist administration would preferably be facilitated intravenously. Alternatively, such treatment could be facilitated in conjunction with parenteral nutrition or dietary therapy assuming the patient is able to eat.
  • 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.
  • 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 secretor
  • 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
  • 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 (I):
  • Xaa at position 28 is Gin or absent; said protein having at least one of the following substitutions: Gin 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,
  • 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, He, Val,
  • 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;
  • 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, He, Phe, Tyr, Ser, Thr, Gly, Gin, Val, or Leu; Ala at position 101 is replaced with Ser, Asn, Gly, His, Pro, Thr, or
  • Gly at position 111 is replaced with Asp
  • Gly at position 118 is replaced with Leu; Gln 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, lie, Phe,
  • Gin at position 139 is replaced with Glu.
  • N-terminally-extended and C-terminally-extended leptins and leptin analogs may also be used in the present invention. Addition of one or a few amino acids to the leptin receptor ligands of the present invention will not appreciably affect the binding of the protein to the leptin receptor.
  • metal-Leptin a leptin with a single methionine added to the N-terminus of the protein, as commonly occurs in some recombinant expression systems, is useful in the present invention. Leptin receptor ligands for use in the present invention may also optionally be 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 solvation 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 leptin receptor ligands 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 + .
  • a further embodiment of the present invention comprises a method for preventing the loss of lean body mass associated with improper nutrition by administration of antibodies to the endogenous leptin receptor which act as leptin receptor agonists to a mammal in need of such treatment.
  • Such antibodies may be monoclonal or polyclonal antibodies to the leptin receptor, so long as their affect is to act as a leptin receptor agonist.
  • Both polyclonal and monoclonal antibodies are obtainable by immunization of an animal with purified leptin receptor or fragments thereof, or purified fusion proteins of leptin receptor, or cells expressing the leptin receptor. 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 using 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.
  • a still further part of this invention is a pharmaceutical composition of matter for administering to a mammal for the prevention or increase in lean body mass that comprises at least one of the leptin receptor agonists 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 its salt can be conveniently administered in the form of a pharmaceutical composition containing one or more leptin receptor agonists 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.
  • the leptin receptor ligands for use in the present invention, or salts thereof, 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 leptin receptor ligands suitable for use in the method of the present invention may effect their prophylactic or therapeutic 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.
  • the formulations of this invention may also include other agents conventional in the art for this type of pharmaceutical formulation.
  • the leptin receptor ligands suitable for use in the present invention may be present in the composition in an broad proportion to the carrier.
  • the leptin receptor ligands may be present in the amount of 0.01 to 99.9 wt%, and more preferably in about 0.1 to 99 wt%.
  • the leptin receptor ligand may be present in an amount of about 1 to 70 wt% of the composition depending on the patient and the amount of muscle loss.
  • the dosage of the leptin receptor agonists, 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 preventing loss of lean body mass associated with improper nutrition 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 leptin receptor ligands 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.
  • leptin receptor ligands suitable for use in the present invention 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 leptin receptor ligands 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 preventing loss of lean body mass 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.
  • Leptin enters the brain by a saturable system independent of insulin. Peptides. 17:305 - 311.
  • Leptin receptor MRNA is expressed in ewe anterior pituitary and adipose tissues and is differentially expressed in hypothalamic regions of well-fed and feed-restricted ewes. Dom. An. Endocrinol. 14:119 - 128.
  • Neuropeptide Y in the area of the hypothalamic paraventricular nucleus activates the pituitary-adrenocortical axis in the rat. Brain Res. 417:33 - 38.
  • Serum leptin is increased in growth hormone-deficient adults: relationship to body composition and effects of placebo-controlled growth hormone therapy for 1 year. Metabolism 46, 812-817.
  • Insulin-like growth factors a role in growth hormone negative feedback and body weight regulation via brain. Sc ience 220, 77-79.

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EP99955171A 1998-10-27 1999-10-27 Verhinderung eines muskelmasseverlust mit liganden des leptinrezeptors Withdrawn EP1128840A1 (de)

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