US20060189522A1 - Modification of feeding behaviour - Google Patents

Modification of feeding behaviour Download PDF

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US20060189522A1
US20060189522A1 US10/541,526 US54152605A US2006189522A1 US 20060189522 A1 US20060189522 A1 US 20060189522A1 US 54152605 A US54152605 A US 54152605A US 2006189522 A1 US2006189522 A1 US 2006189522A1
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nmoles
oxm
subject
glp
body weight
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Stephen Bloom
Mohammad Ghatei
Caroline Small
Catherine Dakin
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Ip2ipo Innovations Ltd
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Imperial Innovations Ltd
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Application filed by Imperial Innovations Ltd filed Critical Imperial Innovations Ltd
Assigned to IMPERIAL COLLEGE INNOVATIONS LIMITED reassignment IMPERIAL COLLEGE INNOVATIONS LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DAKIN, CATHERINE LOUISE, BLOOM, STEPHEN ROBERT, SMALL, CAROLINE JANE, GHATEI, MOHAMMAD ALI
Publication of US20060189522A1 publication Critical patent/US20060189522A1/en
Priority to US11/781,773 priority Critical patent/US7825091B2/en
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Priority to US12/875,636 priority patent/US20110021420A1/en
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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
    • 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
    • A61K38/2271—Neuropeptide Y
    • 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
    • A61K38/26—Glucagons
    • 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
    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61P3/06—Antihyperlipidemics

Definitions

  • the present invention relates to compositions and methods for use in weight loss in mammalian animals.
  • Preproglucagon is a 160 amino acid polypeptide which is cleaved in a tissue specific manner by prohormone convertase-1 and -2 giving rise to a number of products with a variety of functions in both the central nervous system (CNS) and peripheral tissues.
  • CNS central nervous system
  • the major post-translational products of preproglucagon cleavage are glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2 (GLP-2), glicentin and oxyntomodulin (OXM), as shown in Figure A. While GLP-1 and GLP-2 have been shown to inhibit food intake, no such role has been demonstrated in humans for the distinct peptide OXM. The importance of OXM as a biologically active peptide in humans has not been demonstrated.
  • the present invention is based on our surprising observations that the OXM peptide can inhibit food intake, reduce weight and increase energy expenditure in humans, and also that OXM infusion suppresses fasting plasma ghrelin.
  • the present invention provides a method for the prevention or treatment of excess weight in a mammal, the method comprising administering a composition comprising OXM to a mammal.
  • the mammal is likely to be in need of prevention or treatment of excess weight.
  • the weight loss may be cosmetic.
  • the composition comprising OXM will be administered in an effective concentration.
  • the present invention also provides the following methods of treatment of a subject: a method for decreasing calorie intake in a subject, a method for decreasing appetite in a subject, a method for decreasing food intake in a subject, a method for weight control or treatment in a subject, a method for reduction or prevention of obesity, and a method for increasing energy expenditure; in particular any one or more of the following: preventing and reducing weight gain; inducing and promoting weight loss; and reducing obesity as measured by the Body Mass Index.
  • the methods include control of any one or more of appetite, satiety, hunger and energy expenditure, in particular any one or more of the following: reducing, suppressing and inhibiting appetite; inducing, increasing, enhancing and promoting satiety and sensations of satiety; and reducing, inhibiting and suppressing hunger and sensations of hunger; and increasing energy expenditure.
  • the methods further include maintaining any one or more of a desired body weight, a desired Body Mass Index, a desired appearance and good health.
  • OXM is administered to a subject, generally by a peripheral route of administration.
  • the present invention also provides a method for improving lipid profile in a subject.
  • the method includes administering to the subject an effective amount of OXM.
  • An improvement in lipid profile includes, but is not limited to, at least one method of reducing cholesterol levels, reducing triglyceride levels and increasing HDL cholesterol levels.
  • OXM can be administered peripherally, such as in a single or divided dose.
  • a method for alleviating a condition or disorder which can be alleviated by reducing nutrient availability and/or increasing energy expenditure.
  • the method includes administering to a subject a therapeutically effective amount of OXM.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising OXM and a pharmaceutically suitable carrier, in a form suitable for oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation.
  • parenteral eg intravenous, intramuscular, or intraperitoneal
  • mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation.
  • the dose per unit may be, for example, as described below or as calculated on the basis of the per kg doses given below.
  • the present invention also includes OXM or an agonist thereof for use in the manufacture of a medicament for administration by a route peripheral to the brain for any of the methods of treatment described above.
  • peripheral routes include oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation.
  • Preferred dose amounts of OXM for the medicaments are given below.
  • the present invention provides a method for cosmetic weight loss in a mammal, the method comprising administering a composition comprising OXM to a mammal.
  • the weight loss is purely for the purposes of cosmetic appearance.
  • the present invention further provides the use, in combination, of OXM and another agent that has an influence in any way on weight and/or food intake, for example, an agent that has any one of more of the following effects: reduces food intake and/or reduces hunger, reduces weight, reduces or prevents obesity, increases energy expenditure or reduces nutrient availability in a mammal, especially a human.
  • the other agent is, for example, GLP-1 or an agonist thereof receptor, or PYY or an agonist thereof, or another substance that is or is derived from a naturally food influence substance, for example, amylin, leptin, exendin-4 or agonists thereof.
  • more than one other agent may be used in combination with OXM, for example, GLP-1 or an agonist thereof and PYY or an agonist thereof may be used.
  • OXM OXM
  • GLP-1 or an agonist thereof PYY or an agonist thereof
  • PYY or an agonist thereof PYY or an agonist thereof
  • OXM is administered in an amount effective to achieve the desired result, as is any other agent used in combination with OXM.
  • the subject generally a human, may be overweight and/or may be diabetic.
  • Figure A is a graphical representation of preproglucagon and its component parts.
  • FIG. 1 is a comparison of the effects of ICV and iPVN proglucagon-derived and related products on food intake in fasted rats.
  • FIG. 1A illustrates the cumulative food intake (g) up to 8 h after ICV injection of GLP-1, OXM, glucagon, or glicentin (all 3 nmol) into fasted animals. *, P ⁇ 0.05 vs. saline control.
  • FIG. 1B illustrates cumulative food intake (g) up to 24 h after an acute iPVN injection of GLP-1, OXM (both 1 nmol), or exendin-4 (0.03 nmol) into fasted animals. *, P ⁇ 0.01 vs. saline control for all groups at 1, 2, and 4 h. *, P ⁇ 0.05 vs. saline control for exendin-4 only at 8 h.
  • FIG. 2 shows two graphs of the effects of ICV and iPVN OXM on food intake in fasted rats.
  • FIG. 2A cumulative food intake (g) up to 8 h after an acute ICV injection of OXM (0.3, 1, 3, or 10 nmol).
  • FIG. 2B cumulative food intake (g) up to 8 h after an acute iPVN injection of OXM (0.1, 0.3, or 1.0 nmol) into fasted animals.
  • * P ⁇ 0.05 vs. saline control.
  • FIG. 3 shows two bar graphs of the effect of ICV OXM at the onset of the dark phase.
  • Sated rats received an ICV injection of OXM, GLP-1 (3 nmol), or saline at the onset of the dark phase.
  • Food intake (grams; A) and behaviors (3) at 1 h postinjection were determined. *, P ⁇ 0/05 vs. saline control.
  • FIG. 4 shows two bar graphs of the inhibition of OXM and GLP-1 effects on food intake by exendin-(9-39).
  • FIG. 4A food intake 1 h after an acute ICV injection of GLP-1 (3 nmol), GLP-1 plus exendin-(9-39) (30 nmol), OXM (3 nmol), OXM and exendin-(9-39) (30 nmol), or exendin-(9-39) alone (30 nmol).
  • FIG. 4A food intake 1 h after an acute ICV injection of GLP-1 (3 nmol), GLP-1 plus exendin-(9-39) (30 nmol), OXM (3 nmol), OXM and exendin-(9-39) (30 nmol), or exendin-(9-39) alone (30 nmol).
  • FIG. 4A food intake 1 h after an acute ICV injection of GLP-1 (3 nmol), GLP-1 plus exendin-(9-39) (30 nmol), OXM (3
  • FIG. 5 is a graph of the competition of [ 125 I] GLP-1 binding in rat hypothalamic membranes by GLP-1 and OXM.
  • FIG. 7 illustrates the effect of twice daily IP injections of OXM (50 nmol/kg) or saline for seven days on a) cumulative food intake (g); and b) body weight gain (g).
  • FIG. 9 illustrates the effect of increasing doses of OXM (0.01-1.0 nmole) on 1 hour food intake when administered into the arcuate nucleus of 24-hour fasted rats. *P ⁇ 0.05, **P ⁇ 0.01, ***P ⁇ 0.05 vs. saline.
  • FIG. 10 illustrates the effect of iARC administration of exendin 9-39 (5 nmoles) or saline injected 15 minutes prior to IP administration of OXM (30 nmol/kg), GLP-1 (30 nmol/kg) or saline on 1 hour food intake (g).
  • FIG. 11 a illustrates the expression of fos-like immunoreactivity in response to A) IP saline or B) IP OXM (50 nmol/kg) in the arcuate nucleus of the hypothalamus (x40 magnification). ***P ⁇ 0.005 vs. saline; and
  • FIG. 11 b illustrates the expression of fos-like immunoreactivity in response to A) IP saline, B) IP OXM (50 nmol/kg) or C) IP CCK (15 nmol/kg) in the NTS and AP of the brainstem.
  • FIG. 12 shows the protocol of the study of the effect of intravenous infusion of OXM on food intake in human subject.
  • the scale represents time (min).
  • Infusion of OXM (3.0 pmol/kg/min) and saline was from 0-90 minutes.
  • the buffet meal was presented at 75 minutes.
  • FIG. 13 shows the calories consumed by the human subject at the buffet meal.
  • Each line represents the calories consumed by an individual subject with saline and OXM infusion.
  • the bold line shows the mean calorie intake for all volunteers.
  • the mean fall in calories with OXM infusion is 17.6 ⁇ 5.7%.
  • FIG. 14 is a visual analogue scale showing the response of the human subjects to the question ‘How hungry are you right now?’ There was a significant fall in subjective hunger during OXM infusion. Hunger scores diminished considerably following the buffet meal.
  • FIG. 15 shows the effect of IP administration of OXM (30 nmoles/kg and 100 nmoles/kg) on fasting plasma ghrelin-IR 30 and 90 minutes post-injection in rats.
  • the solid blocks show the results with the saline control, the hatched block the results with OXM.
  • FIG. 16 shows energy intake in kJ calories consumed by human subjects at a buffet meal.
  • Each line represents the energy intake of an individual subject with saline and with OXM infusion.
  • the bold line shows the mean calorie intake for all volunteers.
  • FIG. 17 shows the energy intake at the buffet meal, and the cumulative 12 and 24 hour energy intake of human subjects.
  • the solid blocks show the results with the saline control, the hatched block the results with OXM.
  • FIG. 18 shows the relative hunger scores of the human subjects during a fasting period and after a meal, with infusion of OXM or a saline control for the period shown.
  • FIG. 19 shows the OXM-like immunoreactivity (OLI) in pmol/L determined by an RIA during a fasting period and after a meal, with infusion of OXM or a saline control for the period shown.
  • OLI OXM-like immunoreactivity
  • FIG. 20 shows gel permeation analysis of plasma samples during OXM infusion.
  • the single immunoreactive peak elutes at the same position as synthetic OXM.
  • FIG. 21 shows the change in plasma ghrelin levels during a fasting period and after a meal, with infusion of OXM or a saline control for the period shown.
  • the present invention is based on the surprising observation that, found that contrary to expectations, the OXM peptide can inhibit food intake and reduce weight.
  • OXM oxygen transfer protein
  • OXM sequences are well known and documented in the art.
  • the present invention relates to all of the sequences recited herein including, in particular, the OXM human sequence SEQ ID NO: 1 (which is the same as the reat, hamster and bovine OXM sequence), as follows: SEQ ID NO: 1 His Ser Gln Gly Thr Phe Thr Ser Asp Tyr Ser Lys Tyr Leu Asp Ser Arg Arg Ala Gln Asp Phe Val Gln Trp Leu Met Asn Thr Lys Arg Asn Lys Asn Ile Ala the OXM angler fish sequence SEQ ID NO: 2 as follows: SEQ ID NO: 2 His Ser Glu Gly Thr Phe Ser Asn Asp Tyr Ser Lys Tyr Leu Glu Asp Arg Lys Ala Gln Glu Phe Val Arg Trp Leu Met Asn Asn Lys Arg Ser Gly Val Ala Glu and the eel OXM sequence SEQ ID NO: 3 as follows: SEQ ID
  • OXM used in this text also covers any analogue of the above OXM sequence, wherein the histidine residue at position 1 is maintained or replaced by an aromatic moiety carrying a positive charge or a derivative thereof, preferably wherein the moiety is an amino acid, more preferably wherein it is a histidine derivative, while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 or 22 of the other amino acids in the above OXM sequence can be independently replaced by any other independently chosen amino acid, with the exception of histidine in position 1.
  • any one or more (to 22) other alpha-amino acid residue in the sequence can be independently replaced by any other one alpha-amino acid residue.
  • any amino acid residue other than histidine is replaced with a conservative replacement as well known in the art i.e. replacing an amino acid with one of a similar chemical type such as replacing one hydrophobic amino acid with another.
  • 1 to 22 of the amino acids can be replaced. In addition to the replacement option above, this may be by a non-essential or modified or isomeric form of an amino acid.
  • 1 to 22 amino acids can be replaced by an isomeric form (for example a D-amino acid), or a modified amino acid, for example a nor-amino acid (such as norleucine or norvaline) or a non-essential amino acid (such as taurine).
  • 1 to 22 amino acids may be replaced by a corresponding or different amino acid linked via its side chain (for example gamma-linked glutamic acid). For each of the replacements discussed above, the histidine residue at position 1 is unaltered or defined above.
  • 1, 2, 3, 4 or 5 of the amino acid residues can be removed from the OXM sequence with the exception of histidine at the 1 position (or as defined above).
  • the deleted residues may be any 2, 3, 4 or 5 contiguous residues or entirely separate residues.
  • the C-terminus of the OXM sequence may be modified to add further amino acid residues or other moieties.
  • the OXM above may be provided as the corresponding salt thereof.
  • pharmaceutically acceptable salts of OXM and its analogues include those derived from organic acids such as methanesulphonic acid, benzenesulphonic acid and p-toluenesulphonic acid, mineral acids such as hydrochloric and sulphuric acid and the like, giving methanesulphonate, benzenesulphonate, p-toluenesulphonate, hydrochloride and sulphate, and the like, respectively or those derived from bases such as organic and inorganic bases.
  • suitable inorganic bases for the formation of salts of compounds for this invention include the hydroxides, carbonates, and bicarbonates of ammonia, lithium, sodium, calcium, potassium, aluminium, iron, magnesium, zinc and the like. Salts can also be formed with suitable organic bases.
  • bases suitable for the formation of pharmaceutically acceptable base addition salts with compounds of the present invention include organic bases which are nontoxic and strong enough to form salts.
  • Such organic bases are already well known in the art and may include amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; tris(hydroxymethyl) aminomethane; and the like.
  • amino acids such as arginine and lysine, mono-, di-, or trihydroxyalkylamines such as mono-, di-, and triethanolamine, choline, mono-, di-, and trialkylamines, such as methylamine, dimethylamine, and trimethylamine, guanidine; N-methylglucosamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzy
  • Salts may be prepared in a conventional manner using methods well known in the art. Acid addition salts of said basic compounds may be prepared by dissolving the free base compounds in aqueous or aqueous alcohol solution or other suitable solvents containing the required acid. Where OXM contains an acidic function a base salt of said compound may be prepared by reacting said compound with a suitable base. The acid or base salt may separate directly or can be obtained by concentrating the solution eg. by evaporation. OXM may also exist in solvated or hydrated forms.
  • the OXM of the present invention may be conjugated to one or more groups such as a lipid, sugar, protein or polypeptide.
  • the OXM can be conjugated by being attached to the group (for example via a covalent or ionic bond) or can be associated therewith.
  • the conjugated link is preferably not through the C or N terminus amino acid, when the OXM is attached to the group.
  • the OXM can be conjugated to a polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, polyoxyethylene-polyoxypropylene copolymers, polysaccharides such as cellulose, cellulose derivatives, chitosan, acacia gum, karaya gum, guar gum, xanthan gum, tragacanth, alginic acid, carrageenan, agarose, and furcellarans, dextran, starch, starch derivatives, hyaluronic acid, polyesters, polyamides, polyanhydrides, and polyortho esters.
  • a polymer such as polyethylene glycol, polyvinylpyrrolidone, polyvinylalcohol, polyoxyethylene-polyoxypropylene copolymers, polysaccharides such as cellulose, cellulose derivatives, chitosan, acacia gum, karaya gum, guar gum, xanthan gum
  • the OXM can be chemically modified.
  • the amino acid side chains, the N terminus and/or the C acid terminus of OXM can be modified.
  • the OXM can undergo one or more of alkylation, disulphide formation, metal complexation, acylation, esterification, amidation, nitration, treatment with acid, treatment with base, oxidation or reduction. Methods for carrying out these processes are well known in the art.
  • the OXM is provided as a lower alkyl ester, a lower alkyl amide, a lower dialkyl amide, an acid addition salt, a carboxylate salt or an alkali addition salt thereof.
  • the amino or carboxylic termini of the OXM may be derivatised by for example, esterification, amidation, acylation, oxidation or reduction.
  • the carboxylic terminus of the OXM can be derivatised to form an amide moiety.
  • the OXM can be treated with metals, in particular with divalent metals.
  • the OXM can therefore be provided in the presence of one or more of the following metals, zinc, calcium, magnesium, copper, manganese, cobalt, molybdenum or iron.
  • the OXM can be provided in the form of a pharmaceutical composition in combination with a pharmaceutically acceptable carrier or diluent.
  • Suitable carriers and/or diluents are well known in the art and include pharmaceutical grade starch, mannitol, lactose, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, (or other sugar), magnesium carbonate, gelatin, oil, alcohol, detergents, emulsifiers or water (preferably sterile).
  • the composition may be a mixed preparation of a composition or may be a combined preparation for simultaneous, separate or sequential use (including administration).
  • the OXM can be provided as a crystalline solid, a powder, an aqueous solution, a suspension or in oil.
  • compositions according to the invention for use in the aforementioned indications may be administered by any convenient method, for example by oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation, and the compositions adapted accordingly.
  • composition can be formulated as liquids or solids, for example solutions, syrups, suspensions or emulsions, tablets, capsules and lozenges.
  • a liquid formulation will generally consist of a suspension or solution of the compound or physiologically acceptable salt in a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
  • a suitable aqueous or non-aqueous liquid carrier(s) for example water, ethanol, glycerine, polyethylene glycol or an oil.
  • the formulation may also contain a suspending agent, preservative, flavouring or colouring agent.
  • a composition in the form of a tablet can be prepared using any suitable pharmaceutical carrier(s) routinely used for preparing solid formulations.
  • suitable pharmaceutical carrier(s) include magnesium stearate, starch, lactose, sucrose and microcrystalline cellulose.
  • a composition in the form of a capsule can be prepared using routine encapsulation procedures.
  • powders, granules or pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier(s), for example aqueous gums, celluloses, silicates or oils and the dispersion or suspension then filled into a soft gelatin capsule.
  • compositions for oral administration may be designed to protect the active ingredient against degradation as it passes through the alimentary tract, for example by an outer coating of the formulation on a tablet or capsule.
  • compositions including compositions for subcutaneous administration, comprise a solution or suspension of the compound or physiologically acceptable salt in a sterile aqueous or non-aqueous carrier or parenterally acceptable oil, for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • a sterile aqueous or non-aqueous carrier or parenterally acceptable oil for example polyethylene glycol, polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil.
  • the solution can be lyophilised and then reconstituted with a suitable solvent just prior to administration.
  • compositions for nasal or oral administration may conveniently be formulated as aerosols, drops, gels and powders.
  • Aerosol formulations typically comprise a solution or fine suspension of the active substance in a physiologically acceptable aqueous or non-aqueous solvent and are usually presented in single or multidose quantities in sterile form in a sealed container, which can take the form of a cartridge or refill for use with an atomising device.
  • the sealed container may be a unitary dispensing device such as a single dose nasal inhaler or an aerosol dispenser fitted with a metering valve which is intended for disposal once the contents of the container have been exhausted.
  • the dosage form comprises an aerosol dispenser, it will contain a pharmaceutically acceptable propellant.
  • the aerosol dosage forms can also take the form of a pump-atomiser.
  • compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.
  • compositions for rectal or vaginal administration are conveniently in the form of suppositories (containing a conventional suppository base such as cocoa butter), pessaries, vaginal tabs, foams or enemas.
  • compositions suitable for transdermal administration include ointments, gels, patches and injections including powder injections.
  • composition is in unit dose form such as a tablet, capsule or ampoule.
  • OXM may be administered peripherally at a dose of, for example, 0.1 nmoles or more per kg body weight of the subject, for example, 0.2 nmoles or more, for example, 0.5 nmoles or more, for example, 1 nmole or more, for example, 1.5 nmoles or more, for example, 2 nmole or more, for example, 2.5 nmoles or more, for example, 3 nmoles or more, for example, 4 nmoles or more, for example, 5 nmoles or more, for example, 6 nmoles or more, for example, 7 nmoles or more, for example, 8 nmoles or more, for example, 9 nmoles or more, for example, 10 nmoles, for example, 11 nmoles or more, for example, up to 12 nmoles per kg body weight.
  • the amount used may be up to 11 nmoles per kg body weight, for example, up to 10 nmoles, for example, up to 9 nmoles, for example, up to 8 nmoles, for example, up to 7 nmoles, for example, up to 6 nmoles, for example, up to 5 nmoles, for example, up to 4 nmoles, for example, up to 3 nmoles, for example, up to 2 nmoles, for example, up to 1 nmoles, for example, up to 0.5 nmoles, for example, up to 0.4 nmoles, for example, up to 0.2 nmoles per kg body weight.
  • the dose is generally in the range of from 0.1 to 12 nmoles per kg body weight, for example, within any combination of upper and lower ranges given above.
  • a dose may be calculated on an individual basis or on the basis of a typical subject, often a 70 or 75 kg subject.
  • the dose may be administered before each meal.
  • a dose of OXM within the range of from 100 nmol to 500 nmol i.e. about 0.5 mg to about 2 mg, which dose is calculated on the basis of a 75 kg subject, may be administered, generally before meals.
  • a pharmaceutical preparation in unit dosage form for peripheral administration preferably comprises an amount of OXM calculated on the basis of the per kg doses given above.
  • the dose may be calculated on the basis of a 70 or 75 kg subject.
  • a composition for subcutaneous administration may comprise a unit dose of OXM within the range of from 100 nmol to 500 nmol i.e. about 0.5 mg to about 2 mg, calculated on the basis of a 75 kg subject.
  • the OXM can be used as a prophylaxis to prevent excess weight gain or can be used as a therapeutic to lose excess weight.
  • the excess weight is typically obesity, although the mammal will not be certified as clinically obese in order to be suffering from excess weight.
  • the OXM may be in liquid, solid or semi-solid form.
  • the mammal is a human, although it may also include other mammalian animals, such as horses, canine animals (in particular domestic canine animals), feline animals (in particular domestic feline animals) as well as mammals which are produced for meat, such as porcine, bovine and ovine animals.
  • the present invention can be used to prevent excess weight in such animals in order to maximise lean meat production.
  • prevention means any effect which mitigates any excess weight, to any extent.
  • treatment means amelioration of excess weight, to any extent.
  • Suitable doses of OXM include those that raise the concentration of OXM significantly above the basal concentration of OXM, such as, but not limited to, a dose that that mimic postprandial serum concentrations of OXM.
  • OXM is administered to a reduction in calorie intake, food intake, or appetite equivalent to the reduction in calorie intake, food intake, or appetite, or to increase the energy expenditure, caused by the postprandial level of OXM.
  • the dose of OXM can be based on the physiological levels observed post-prandially.
  • a single dose may be administered per day, or divided doses can be used (see above).
  • OXM OXM
  • a peripheral route of administration that is to say, via a route other than directly to the brain.
  • routes include oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising OXM and a pharmaceutically suitable carrier, in a form suitable for oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation. If in unit dosage form, the dose may per unit may be calculated on the basis of the per kg doses given above.
  • the present invention also includes OXM or an agonist thereof for use in the manufacture of a medicament for administration by a peripheral route for any of the methods of treatment described above.
  • peripheral routes include oral, rectal, parenteral eg intravenous, intramuscular, or intraperitoneal, mucosal e.g. buccal, sublingual, nasal, subcutaneous or transdermal administration, including administration by inhalation.
  • Preferred dose amounts of OXM for the medicaments are given above.
  • the present invention provides a method for cosmetic weight loss in a mammal, the method comprising administering a composition comprising OXM to a mammal.
  • the weight loss is purely for the purposes of cosmetic appearance.
  • the present invention provides the prevention or treatment of excess weight by the administration of OXM which acts as an inhibitor to food intake to the mammalian body and/or increases energy expenditure. Such reduced food intake and/or increased energy expenditure results in the prevention or treatment of excess weight in a mammal.
  • food includes a substance which is ingested and which has calorific value.
  • OXM infusion suppresses fasting plasma ghrelin. This is an important finding because ghrelin is a powerfill stimulant of appetite in man and preprandial rises in plasma ghrelin have been suggested to be a trigger for meal initiation. Without being bound by the hypothesis, we consider that inhibition of the normal preprandial rise in ghrelin by OXM is likely to be one mechanism by which OXM infusion reduces appetite.
  • the present invention further provides the use, in combination, of OXM and another agent that has an influence in any way on weight and/or food intake, for example, an agent that has any one of more of the following effects: reduces food intake and/or reduces hunger, reduces weight, reduces or prevents obesity, increases energy expenditure or reduces nutrient availability in a mammal, especially a human.
  • the other agent is, for example, GLP-1 or an agonist thereof receptor, or PYY or an agonist thereof, or another substance that is or is derived from a naturally food influence substance, for example, amylin, leptin, exendin-4 or agonists thereof.
  • more than one other agent may be used in combination with OXM, for example, GLP-1 or an agonist thereof and PYY or an agonist thereof may be used.
  • OXM OXM
  • GLP-1 or an agonist thereof PYY or an agonist thereof
  • PYY or an agonist thereof PYY or an agonist thereof
  • OXM may be used with GLP-1 or an agonist thereof. OXM appears to have an arcuate site of action, whereas GLP-1 acts via the brain stem. The use of the two agents in combination may give a synergistic effect.
  • GLP-1 like OXM, is a post-translational product of preproglucagon, see Figure A.
  • the initial post-translational product is GLP-1 (1-37).
  • Human GLP-1 (1-37) has the following amino acid sequence, SEQ ID NO: 4:
  • GLP-1 (1-36) SEQ.ID.NO: 5 and the amide thereof GLP-1 (1-36) NH 2 ; GLP-1 (7-37) SEQ.ID.NO:6; and GLP-1 (7-36) SEQ.ID.NO:7 and the amine thereof, GLP-1 (7-36) NH 2 , which is the most biologically active of the GLP-1 peptides.
  • GLP-1 is used herein to denote any of the GLP-1 peptides defined above, especially GLP-1 (7-36) NH 2 , also known as GLP-1 (7-36) amide.
  • the terms encompasses GLP-1 peptides of any animal origin, especially the human peptides.
  • a GLP-1 agonist is a peptide, small molecule, or chemical compound that preferentially binds to the GLP-1 receptor and stimulates the same biological activity as does GLP-1.
  • an agonist for the GLP-1 receptor binds to the receptor with an equal or greater affinity than GLP-1.
  • an agonist selectively binds the GLP-1 receptor, as compared to binding to another receptor.
  • Exendin-4 which is a 39-amino acid peptide isolated from the salivary glands of the Gila monster ( Heloderma suspectum ) (Eng J et al J Biol Chem 267:7402-7405, 1992) is an example of an agonist at the GLP-1 receptor.
  • GLP-1 agonists include GLP-1 related peptides and peptides that result from natural or synthetic enzymatic or chemical processing of preproglucagon or of a GLP-1 peptide or a related peptide.
  • Any compound that is described as being a GLP-1 agonist may be used in the present invention, as may any compound that is tested for GLP-1 agonist activity, for example, as described above, and found to function as a GLP-1 agonist.
  • a recombinant GLP-1 receptor suitable for use in screening is disclosed in WO93/19175. Many GLP-1 agonists are known and are described in the art.
  • GLP-1 agonists examples include Arg34, Lys26(N-epsilon-(gamma-Glu(N-alpha-hexadecanoyl)))-GLP-1 (7-37), IP7-GLP-1 (7-37)OH.
  • PYY has a sustained duration of action, for example, when administered peripherally, it continues to act after it has been cleared from the circulating blood, for example, for up to 24 hours after administration. Accordingly, PYY is effective when two or even one dose per day is administered. Without being limited by the following, OXM appears to have an immediate effect, which may not be sustained for a prolonged period. OXM may be administered several times per day, for example, before a meal. The use of long acting PYY with short acting OXM enables “fine tuning” of administration regimes to the needs of the user.
  • PYY is a 36-residue peptide amide isolated originally from porcoine intestine (Tatemoto et al. Proc. Natl. Acad. Sci. 79:2514, 1982).
  • the term as used herein includes PYY obtained or derived from any species.
  • PYY includes the human full length polypeptide, which has the following sequence, SEQ ID NO: 8:
  • PYY agonists do not include NPY.
  • PYY as used herein also includes PYY 3-36 . It may be advantageous to use PYY 3-36 .
  • a PYY agonist is any compound which binds to a receptor that specifically binds PYY, and elicits an effect of PYY.
  • a PYY agonist is a compound that affects food intake, caloric intake, or appetite, and/or which binds specifically in a Y receptor assay or competes for binding with PYY, such as in a competitive binding assay with labeled PYY.
  • PYY agonists include, but are not limited to, compounds that bind to the Y2 receptor.
  • PYY agonists and compounds that may be used as PYY agonists are disclosed in the art.
  • contemplated as useful PYY agonists are Y2 specific NPY peptide agonists as described in U.S. Pat. No. 5,026,685; U.S. Pat. No. 5,574,010; U.S. Pat. No. 5,604,203; U.S. Pat. No. 5,696,093; U.S. Pat. No. 6,046,167.
  • variants of PYY and of neuropeptide Y are analogous to the variants and modifications of OXM described above.
  • OXM may be used in with both GLP-1 or an agonist thereof and PYY or an agonist thereof.
  • any of OXM and GLP-1 or an agonist thereof and PYY or an agonist thereof may serve to increase the effectiveness of any of the agents compared with its use alone, for example, as described above.
  • use of the two or three agents in combination may reduce any tendency for “escape” when using an agent alone.
  • the term “escape” is used to denote a reduction in effect of an agent with time. For example, if any one of the agents above has been used alone, its effect may reduce with time.
  • Use of one or both of the other agents in addition may reduce or prevent the tendency for that reduction in effectiveness.
  • PYY has a sustained effect and may be used for prolonged periods. If the effect of PYY should appear to reduce, or to reduce or prevent any such reduction in effect, OXM may be administered in addition to the PYY.
  • GLP-1 may also be used for the same purpose, with OXM or with OXM and PYY.
  • an additional appetite suppressant may also be administered.
  • an additional appetite suppressant include amfepramone (diethylpropion), phentermine, mazindol and phenylpropanolamine, fenfluramine, dexfenfluramine, and fluoxetine.
  • OXM When used in combination with another agent, OXM may be administered simultaneously or substantially simultaneously as the other agent, or sequentially, in either order.
  • OXM and the other agent may be administered in a single pharmaceutical composition or in separate compositions, and they may be administered by the same route or by different routes. It is generally more convenient to administer all the active agents in a single composition. However, in some cases it may be necessary or appropriate to administer the active agents by different routes.
  • peptides are generally not stable on oral administration unless modified or formulated in a special way, so must generally be administered via a non-oral route.
  • Some agonists for example, GLP-1 agonists, are chemical compounds that are stable when administered orally. It may be appropriate to administer OXM non-orally and the other component by a non-oral route.
  • a therapeutically effective amount of OXM or an agonist thereof is administered with a therapeutically effective amount of GLP-1 or an agonist thereof and/or PYY or an agonist thereof.
  • GLP-1/PYY is used herein to denote GLP-1 or an agonist thereof and/or PYY or an agonist thereof.
  • the OXM or agonist thereof and the GLP-1/PYY may be administered simultaneously or substantially simultaneously, or sequentially, in any order.
  • the OXM or agonist thereof and the GLP-1/PYY may be administered in a single pharmaceutical composition or in separate compositions, and they may be administered by the same route or my different routes.
  • the OXM and the GLP-1/PYY are to be administered in a single pharmaceutical composition
  • that composition may be any of those described above for OXM or an agonist thereof.
  • the composition may enable simultaneous or substantially simultaneous administration of the OXM or agonist thereof and the GLP-1/PYY.
  • the OXM or agonist thereof and the GLP-1/PYY may be compartmentalized in the composition, for example, in different layers of a tablet, or in different granules in a capsule. If desired, such compartmentalization may be designed to give different release properties to the components to enable delivery of the OXM or agonist component and the GLP-1/PYY at different times, for example, sequentially.
  • the OXM or agonist thereof and the GLP-1/PYY may be formulated in separate pharmaceutical compositions, for example, any of the pharmaceutical compositions described above for OXM and agonists thereof.
  • Such separate compositions may be administered simultaneously or substantially simultaneously, or they may be administered sequentially, in any order.
  • PYY may be administered two times or even once per day, with OXM being administered up to several times per day, for example, before meals.
  • the OXM or agonist thereof and the GLP-1/PYY may be administered by the same route or by different routes, for example, as described above.
  • OXM may be used in a dose as disclosed above in relation to peripheral administration when used alone, that is to say, OXM may be administered peripherally at a dose of, for example, 0.1 nmoles or more per kg body weight of the subject, for example, 0.2 nmoles or more, for example, 0.5 nmoles or more, for example, 1 nmole or more, for example, 1.5 nmoles or more, for example, 2 nmole or more, for example, 2.5 nmoles or more, for example, 3 nmoles or more, for example, 4 nmoles or more, for example, 5 nmoles or more, for example, 6 nmoles or more, for example, 7 nmoles or more, for example, 8 nmoles or more, for example, 9 nmoles or more, for example, 10 nmoles, for example, 11 nmoles or more, for example, up to 12
  • the amount used may be up to 11 nmoles per kg body weight, for example, up to 10 nmoles, for example, up to 9 nmoles, for example, up to 8 nmoles, for example, up to 7 nmoles, for example, up to 6 nmoles, for example, up to 5 nmoles, for example, up to 4 nmoles, for example, up to 3 nmoles, for example, up to 2 nmoles, for example, up to 1 nmoles, for example, up to 0.5 nmoles, for example, up to 0.4 nmoles, for example, up to 0.2 nmoles per kg body weight.
  • the dose is generally in the range of from 0.1 to 12 nmoles per kg body weight, for example, within any combination of upper and lower ranges given above.
  • GLP-1 or an agonist thereof may be administered peripherally at a dose of, for example, 0.1 nmoles or more per kg body weight of the subject, for example, 0.2 nmoles or more, for example, 0.4 nmoles or more, for example, 0.6 nmoles or more, for example, 0.8 nmoles or more, for example, 1.0 nmole or more, for example, 1.2 nmoles or more, for example, 1.4 nmoles or more, for example, 1.6 nmoles or more, for example, 1.8 nmoles or more, for example, 2.0 nmoles or more, for example, 2.2 nmoles or more, for example, 2.4 nmoles or more, for example, 2.6 nmoles or more, for example, 2.8 nmoles, for example, 3.0 nmoles or more, for example, up to 3.2 nmoles per kg body weight.
  • the amount used may be up to 3.0 nmoles per kg body weight, for example, up to 2.8 nmoles, for example, up to 2.6 nmoles, for example, up to 2.4 nmoles, for example, up to 2.2 nmoles, for example, up to 2.0 nmoles, for example, up to 1.8 nmoles, for example, up to 1.4 nmoles, for example, up to 1.2 nmoles, for example, up to 1.0 nmoles, for example, up to 0.8 nmoles, for example, up to 0.6 nmoles, for example, up to 0.4 nmoles, for example, up to 0.2 nmoles per kg body weight.
  • the dose is generally in the range of from 0.1 to 3.2 nmoles per kg body weight, for example, within any combination of upper and lower ranges given above.
  • PYY or an agonist thereof may be used at a dose within the ranges disclosed above for GLP-1.
  • the doses of the various agent may be independent of each other or, for example, equimolar doses may be used, for example, equimolar doses of GLP-1 or an agonist thereof and PYY or an agonist thereof.
  • a dose may be calculated on an individual basis or on the basis of a typical subject, often a 70 or 75 kg subject.
  • a further embodiment of the present invention is a pharmaceutical composition
  • oxyntomodulin and one or more other agents having an influence in any way on weight and/or food intake, for example, an agent that has any one of more of the following effects: reduces food intake and/or reduces hunger, reduces weight, reduces or prevents obesity, increases energy expenditure or reduces nutrient availability in a mammal, especially a human, in admixture or conjunction with a pharmaceutically suitable carrier.
  • the agents are as defined above and are, for example, GLP-1 or an agonist and/or PYY agonist thereof.
  • the compositions may be, for example, as described above for OXM pharmaceutical compositions. Doses of the OXM and other agents are, for example, as described above.
  • a pharmaceutical preparation in unit dosage form for peripheral administration preferably comprises an amount of OXM calculated on the basis of the per kg doses given above.
  • the dose may be calculated on the basis of a 75 kg subject.
  • a composition for subcutaneous administration may comprise a unit dose of OXM within the range of from 100 nmol to 500 nmol i.e. about 0.5 mg to about 2 mg, calculated on the basis of a 75 kg subject.
  • the present invention also provides the use of OXM in the manufacture of a medicament for the treatment of a subject according to any of the methods disclosed above.
  • the medicament may be a single pharmaceutical composition comprising all the components, as described above, or may be a two or more component medicament, one component being a pharmaceutical composition comprising OXM, the other component(s) each being a pharmaceutical composition comprising the other agent(s) that reduce food intake, see above.
  • the medicament whether a one component medicament or a two or more component medicament as described above, will generally be packaged with instructions relating to its use. Such instructions will refer to the timing, dose and route of administration of the component(s).
  • Specific defined dosage ranges can be determined by standard designed clinical trials with patient progress and recovery being fully monitored.
  • Such trials may use an escalating dose design using a low percentage of the maximum tolerated dose in animals as the starting dose in man. Examples of suitable doses are given above.
  • OXM causes a Potent Decrease in Fasting-Induced Refeeding when Injected Both ICV and iPVN
  • GLP-1, glicentin, glucagon, and SP-1 were purchased from Peninsula Laboratories, Inc. (St. Helens, UK). OXM was purchased from IAF BioChem Pharma (Laval, Canada). Exendin-4 and exendin-(9-39) were synthesised at Medical Research Council, Hemostasis Unit, Clinical Sciences Center, Hammersmith Hospital, London, UK using F-moc chemistry on an 396 MPS peptide synthesiser (Advanced ChemTech, Inc.) and purified by reverse phase HPLC on a C 8 column (Phenomex, Macclesfield, UK). The correct molecular weight was confirmed by mass spectrometry. All chemicals were purchases from Merck & Co. (Lutterworth, Sheffield, UK) unless otherwise stated.
  • ICV intracerebraventricularly
  • iPVN into the hypothalamic paraventricular nucleus
  • Exendin-4 when injected ICV, inhibits food intake more potently than GLP-1. Therefore, exendin-4 was injected iPVN at a dose of 0.03 nmol.
  • rats were injected iPVN with saline, GLP-1 (1.0 nmol), or OXM (0.1, 0.3, or 1.0 nmol; n-12-15/group).
  • OXM acts via the GLP-1 receptor
  • a study using the GLP-1 receptor antagonist exendin-(9-39) was performed.
  • rats were injected with ICV with saline, GLP-1 (3 nmol), GLP-1 (3 nmol) plus exendin-(9-39) (30 nmol), OXM (3 nmol), OXM (3 nmol) plus exendin-(9-39) (30 nmol), or exendin-(9-39) alone (30 nmol).
  • Receptor binding assays were performed in a final volume of 0.5 ml rat hypothalamic membranes (200 ⁇ g protein), 500 Bq (100 pM) [ 125 I]GLP-1, and unlabeled competing peptides (GLP-1 and OXM) as specified. Membranes were incubated at room temperature for 90 min. Bound and free radioactivity were separated by centrifugation (2 min, 4° C.). Pelleted membranes were washed with assay buffer (0.5 ml, ice-cold), and the membranes were centrifuged as described above. The supernatant was removed, and the radioactivity in the pellet was counted using a ⁇ -counter.
  • Specific (saturable) binding was calculated as the difference between the amount of [ 125 I]GLP-1 bound in the absence (total binding) and presence of 1 ⁇ m GLP-1 or OXM (nonsaturable binding). All curves were constructed with points in triplicate. IC 50 values were calculated using the Prism 3 program (GraphPad Software, Inc., San Diego, Calif.).
  • the dark phase is the rats' natural feeding time. Therefore, assessing the effect of a putative satiety factor in non-fasted animals at this time would represent a more physiological effect.
  • the affinity (IC 50 ) of GLP-1 for the GLP-receptor in rat hypothalamic membrane preparations was 0.16 nM ( FIG. 5 ).
  • the affinity of OXM for the GLP-1 receptor in the same membrane preparations was 8.2 nM ( FIG. 5 ), which is approximately 2 orders of magnitude weaker than that of GLP-1.
  • OXM causes a potent decrease in fasting-induced refeeding when injected both ICV and iPVN. The effect was sustained until 8 h (iPVN) or 4 h (ICV) postinjection. The effect of OXM is approximately of the same magnitude and time course as that of GLP-1 when administered ICV and iPVN at equimolar doses. In addition, OXM inhibits food intake in nonfasted rats at the onset of the dark phase, and at that time they showed no signs of aversive behaviour.
  • OXM OXM-specific binding site in gastric mucosa.
  • GLP-1 and OXM have similar potency in feeding studies.
  • OXM reduces food intake to the same magnitude.
  • OXM might act through both the GLP-1R and its own receptor in the hypothalamus.
  • OXM could elicit a response comparable to that of GLP-1 despite its lower affinity for the GLP-IR.
  • Exendin-(9-39) a fragment of the GLP-1R agonist exendin-4, is a potent and selective antagonist at the GLP-1R.
  • GLP-1 and exendin-(9-39) are coinjected, the anorectic actions of GLP-1 are blocked.
  • OXM is coinjected with exendin-(9-39), the anorectic effects of OXM are also completely blocked. This would strengthen the argument that OXM is mediating its effects via the GLP-1R.
  • OXM was purchased from IAF BioChem Pharma (Laval, Canada).
  • GLP-1 was purchased from Peninsula Laboratories Inc. (St. Helens, UK).
  • Exendin 9-39 was synthesised at Medical Research Council, Hemostasis Unit, Clinical Sciences Centre, Hammersmith Hospital, London, UK using F-moc chemistry on a 396 MPS peptide synthesizer (Advanced ChemTech Inc., Louisville, Ky.) and purified by reverse phase HPLC on a C 8 column (Phenomex, Macclesfield, UK), using a gradient of acetonitrile on 0.1% trifluoroacetic acid. Correct molecular weight was confirmed by mass spectrometry. All chemicals were purchases from Merck Eurolab Ltd. (Lutterworth, Sheffieldshire, UK), unless otherwise stated.
  • IP Intra-Peritoneal
  • IP injections were delivered using a 1 ml syringe and a 25 gauge needle. The maximum volume of injection was 500 ⁇ l, and was adjusted according the weight of the individual animal. All peptides were dissolved in saline.
  • mice were fasted for 24 hours prior to the study. During the early light phase (09.00-10.00 hr), rats were given a single IP injection of saline, GLP-1 (30 nmol/kg body weight as a positive control) or OXM (10-300 nmol/kg body weight) (n 12 per group) in a volume of 500 ⁇ l. Following the injection, the animals were returned to their home cages and provided with a pre-weighed amount of chow. Food intake was measured 1, 2, 4, 8 and 24 hours post-injection.
  • the dark phase is the “normal” feeding time for rats. Therefore, any inhibition of food intake at this time could be considered to be more physiological than alterations to refeeding following a fast.
  • a laparotomy was rapidly performed and the stomach exposed.
  • the pyloric junction was ligated (2.0 Mersilk, Johnson & Johnson, Belgium), followed by ligation of the gastro-oesophogeal junction and the stomach was removed.
  • the gastric contents were then removed, placed in a pre-weighed weighing boat and left to air-dry for 48 hours.
  • iARC Intra-arcuate
  • 24-hour fasted rats received an iARC injection of saline or exending 9-39 (5 nmoles) followed by an IP injection of saline, OXM (30 nmoles/kg body weight) or GLP-1 (30 nmoles/kg body weight) 15 minutes later.
  • OXM nmoles/kg body weight
  • GLP-1 GLP-1
  • the sections were then mounted on poly-L-lysine-coated slides, dehydrated in increasing concentrations of ethanol (50-100%), delipidated in xylene and coverslipped using DPX mountant.
  • Slides were examined for FLI-positive nuclei using a light microscope (Nikon Eclipse E-800) and images captured using a microimager (Xillix MicroImager).
  • the numbers of FLI-positive nuclei in the hypothalamus and brainstem were counted by an independent member of the research team who was blinded to the experimental groups. The average number of FLI-positive nuclei per section was calculated and expressed as an integer for each animal.
  • a static incubation system was used. Male Wistar rats were killed by decapitation and the whole brain removed immediately. The brain was mounted, ventral surface uppermost, and placed in a vibrating microtome (Microfield Scientific Ltd., Dartmouth, UK). A 1.7 mm slice was taken from the basal hypothalamus, blocked lateral to the Circle of Willis and incubated in chambers containing 1 ml of artificial cerebrospinal fluid which was equilibrated with 95% O 2 and 5% CO 2 . The hypothalamic slice encompassed the medial pre-optic area, PVN (paraventricular hypothalamic nucleus), dorsomedial nucleus, ventromedial nucleus, lateral hypothalamus and ARC.
  • PVN paraventricular hypothalamic nucleus
  • each explant was incubated for 45 minutes in 600 ⁇ l aCSF (basal period) before being challenged with a test period.
  • OXM 100 nM was used as a dose representing a concentration ten times that of its IC 50 for the GLP-1 receptor.
  • the viability of the tissue was confirmed by a final 45-minute exposure to aCSF containing 56 mM KCl.
  • the aCSF was removed and stored at ⁇ 20° C. until measurement of ⁇ MSH-immunoreactivity by radioimmunoassay.
  • Alpha-MSH was measured using an in-house radioimmunoassay, developed using an antibody from Chemicon International Inc.
  • Intraperitoneal administration of OXM (100 nmol/kg and 300 nmol/kg) caused a significant inhibition in refeeding in 24-hour fasted animals one hour post-injection, compared with saline controls (1 hour: OXM 100 nmol/kg, 5.4 ⁇ 0.2 g (P ⁇ 0.05), 300 nmol/kg, 4.5 ⁇ 0.2 g (P ⁇ 0.05) vs. saline, 6.3 ⁇ 0.2 g).
  • the reduction in food intake caused by 100 nmol/kg was sustained until 8 hours post-injection.
  • OXM, 3 and 10 nmol/kg failed to affect food intake at any time-point investigated in nocturnally feeding rats injected immediately prior to the dark phase.
  • OXM, 30 nmol/kg significantly inhibited food intake until 2 hours post-injection (2 hours: OXM, 30 nmol/kg, 4.5 ⁇ 0.4 g vs. saline, 5.8 ⁇ 0.4 g; P ⁇ 0.05).
  • Food intake was reduced 4 hours post-injection, but this was not significant.
  • OXM, 100 nmol/kg significantly inhibited food intake throughout the dark phase (8 hours: OXM, 100 nmol/kg, 14.1 ⁇ 0.8 g vs. saline, 16.9 ⁇ 0.5 g; P ⁇ 0.05) ( FIG. 6 b ).
  • OXM 1.0 nmoles
  • Intraperitoneal administration of both GLP-1 (30 nmol/kg) and OXM (30 nmol/kg) caused a significant inhibition of food intake one hour into the dark phase (1 hour: GLP-1, 5.0 ⁇ 0.6 g, OXM, 5.1 ⁇ 0.4 g vs. saline, 9.2 ⁇ 0.3 g).
  • the anorexia caused by IP administration of OXM was blocked by prior administration of the GLP-1 receptor antagonist, exendin 9-39 (300 nmol/kg), injected directly into the ARC (Table 3 & FIG. 10 ). Inhibition of food intake by IP GLP-1 was not affected by prior iARC administration of exendin 9-39.
  • IP CCK In the brainstem, IP CCK (15 nmol/kg) caused dense staining of FLI, most notably in the NTS (nucleus tractus solitarius) and the area postrema ( FIG. 6 b ). However, neither IP saline nor IP OXM (50 nmol/kg) caused a specific increase in c-fos expression in the same brainstem nuclei investigated ( FIG. 11 b ).
  • OXM causes a reduction in food intake in rats. This was seen following a fast in the light phase and during the nocturnal feeding phase. The anorectic effect was potent and sustained for periods up to 24 hours. Twice-daily IP administration of OXM for seven days caused a reduction in daily food intake compared with those treated with saline, with no tachyphylaxis. Animals treated with OXM gained significantly less weight than pair fed animals, despite the two groups receiving identical daily caloric intake. Intraperitoneal administration of OXM did transiently reduce water intake although this was not sustained, suggesting that the reduction in the rate of body weight gain was not due to dehydration.
  • GLP-1 and OXM are potent inhibitors of gastric emptying in rodents and humans and in the case of GLP-1, this is thought to be the dominant mechanism through which it promotes satiety.
  • OXM was acting in the same way, and that its effects on gastric emptying were the cause of sustained anorexia.
  • peripheral administration of OXM led to a slight delay in gastric emptying in the first hour after the re-introduction of food, this was non-significant and the effect was short-lived. This suggested that OXM does slow gastric emptying, but it is not likely to be responsible for the robust and sustained inhibition of food intake.
  • OXM is potentially important in both long and short-term regulation of food intake and body weight maintenance. Rather than reducing appetite via “traditional” satiety pathways, involving slowing of gastric emptying and activation of brainstem nuclei, circulating OXM is mediating its anorectic effects via direct interaction with the ARC, potentially by activating POMC (pro-opiomelanocortin) neurons within the nucleus. Therefore, OXM may be useful in the treatment or prevention of excess weight such as obesity in mammals, and further represents a novel target for the development of therapeutic agents in the treatment of excess weight such as obesity in mammals.
  • POMC pro-opiomelanocortin
  • the study design was a double-blind placebo-controlled crossover, see FIG. 12 .
  • 13 healthy volunteers (age 27 ⁇ 2 yrs; BMI 25.3 ⁇ 0.7 kg ⁇ 2 ) received a 90 minute intravenous infusion of OXM (3.0 pmol/kg/min) and an infusion of saline ⁇ 1 week apart, in random order.
  • OXM was dissolved in saline containing haemaccel (5% by volume) to reduce adsorption to the syringe and tubing. Volunteers completed a food diary for three days prior to each infusion and for the subsequent 24 hours. Subjects were instructed to follow a similar diet on the days preceding each infusion. They consumed an identical meal (of their choice) on the night before each infusion and fasted from 9 pm.
  • VAS visual analogue scales
  • OXM infusion led to a significant fall in calories consumed at the buffet meal (192 ⁇ 59 kcal; 17.6 ⁇ 5.7%). 12/13 subjects showed a decrease in calories consumed with OXM infusion, see FIG. 13 . OXM infusion was associated with a significant fall in subjective hunger scores, see FIG. 14 (VAS ‘How hungry are you right now?’ 60 min P ⁇ 0.05). There were no adverse effects of OXM infusion. In particular there was no effect of OXM on feelings of sickness (nausea) (VAS ‘How sick do you feel right now?’ 75 min P 0.8). The effect appears to be rapid.
  • OXM or saline were administered to fasted rats to investigate the plasma OXM-IR and ghrelin-IR levels following IP OXM.
  • Plasma OXM-IR levels were measured, using a previously described assay, which also measures enteroglucagon (i.e., N-terminally elongated OXM) (Ghatei M A, Uttenthal L O, Christofides N D, Bryant M G, Bloom S R 1983 J Clin Endocrinol Metab 57:488-495).
  • enteroglucagon i.e., N-terminally elongated OXM
  • the OXM-IR assay could detect changes of 10 pmol/L (95% confidence limit) with an intra-assay variation of 5.7%.
  • the ghrelin radioimmunoassay (English P J, Ghatei M A, Malik I A, Bloom S R, Wilding J P 2002 J Clin Endocrinol Metab 87:2984) measured both octanoyl and des-octanoyl ghrelin (Total ghrelin). It did not cross-react with any known gastrointestinal or pancreatic peptide hormones and could detect changes of 10 pmol/L (95% confidence limit) with an intra-assay variation of 9.5%.
  • IP administration of OXM (30 nmoles/kg and 100 nmoles/kg) increased plasma OXM-IR 30 and 90 minutes post-injection (30 min plasma OXM-IR pmol/L: saline 61.8 ⁇ 8.9, OXM 30 nmoles/kg 448.9 ⁇ 184.4, OXM 100 nmoles/kg 997.1 ⁇ 235.4.
  • the plasma OXM-IR levels were determined in three additional groups: a) Rats fasted overnight and killed at the beginning of the light phase (plasma OXM-IR pmol/L: 51.9 ⁇ 5.8), b) Rats fed high fat rat chow overnight and decapitated at the beginning of the light phase (plasma OXM-IR pmol/L: 220.2 ⁇ 22.2), c) Rats fasted overnight, then given ad libitum access to high fat chow for 2 hours at lights-on, were decapitated at the end of the 2-hour high fat meal (plasma OXM-IR pmol/L: 254.0 ⁇ 32.7).
  • IP administration of OXM (30 nmoles/kg and 100 nmoles/kg) significantly decreased fasting plasma ghrelin-IR 30 and 90 minutes post-injection (30 min plasma ghrelin pmol/L: saline, 1056.9 ⁇ 64.0, OXM, 30 nmoles/kg 867.4 ⁇ 42.0 (p ⁇ 0.01), OXM, 100 nmoles/kg 860.0 ⁇ 47.5 (p ⁇ 0.02).
  • Plasma ghrelin-IR levels were determined in 3 additional groups: a) Rats fasted overnight and killed at the beginning of the light phase (plasma ghrelin-IR pmol/L: 1066.1 ⁇ 80.9), b) Rats fed high fat rat chow overnight and decapitated at the beginning of the light phase (plasma ghrelin-IR pmol/L: 611.3 ⁇ 16.9), c) Rats fasted overnight, at lights-on they were given ad libitum access to high fat chow for 2 h, were decapitated at the end of the 2-hour high fat meal (plasma ghrelin pmol/L: 648.9 ⁇ 57.3).
  • Plasma OLI, pancreatic glucagon, peptide YY (PYY), insulin, glucagon-like peptide-1 (GLP-1) and ghrelin were measured using established in-house RIAs.
  • the OLI assay (Ghatei M A, Uttenthal L O, Christofides N D, Bryant M G, Bloom S R 1983 J Clin Endocrinol Metab 57:488-495) could detect changes of 10 pmol/L (95% confidence limit) with an intra-assay variation of 5.7%.
  • the PYY assay (Adrian T E, Savage A P, Sagor G R, Allen J M, Bacarese-Hamilton A J, Tatemoto K, Polak J M, Bloom S R 1985 Gastroenterology 89:494-499) could detect changes of 2 pmol/L (95% confidence limit) with an intra-assay variation of 5.8%.
  • the PYY antibody was specific for the C-terminus of PYY and cross-reacts fully with human PYY 3-36.
  • the insulin assay (Kreymann B, Williams G, Ghatei M A, Bloom S R 1987 Lancet 2:1300-1304) could detect changes of 6 pmol/L (95% confidence limit) with an intra-say variation of 5.4%.
  • the GLP-1 assay (Kreymann B, Williams G, Ghatei M A, Bloom S R 1987 Lancet 2:1300-1304) could detect changes of 8 pmol/L (95% confidence limit) with an intra-assay variation of 6.1%.
  • the GLP-1 antibody was specific for amidated GLP-1 and does not cross-react with GLP-1 (1-37), GLP-1 (1-36) or GLP-1 (7-37).
  • the ghrelin assay (English P J, Ghatei M A, Malik I A, Bloom S R, Wilding J P 2002 J Clin Endocrinol Metab 87:298) could detect changes of 10 pmol/L (95% confidence limit) with an intra-assay variation of 9.5%.
  • Plasma leptin was measured using the Linco Research (Missouri, USA) human leptin RIA kit.
  • ghrelin levels increased throughout the fasting period (t 0 461 ⁇ 32 pmol/L, t 75 484 ⁇ 35 pmol/L) and decreased postprandially (t 225 357 ⁇ 28 pmol/L).
  • fasting levels of ghrelin decreased before the meal (t 0 482 ⁇ 33 pmol/L, t 75 435 ⁇ 35 pmol/L) and there was a further postprandial reduction in ghrelin (t 225 356 ⁇ 31 pmol/L).
  • plasma ghrelin prior to the buffet meal was significantly reduced by OXM infusion compared to saline (mean change in ghrelin from t 0 to t 75 : saline+24 ⁇ 10 pmol/L, OXM minus 47 ⁇ 11 pmol/L, P ⁇ 0.0001) ( FIG. 21 ).
  • the suppression in plasma ghrelin due to OXM infusion represents 44 ⁇ 10% of the postprandial decrease in ghrelin on the corresponding saline infusion day (mean postprandial decrease 155 ⁇ 19 pmol/L).
  • Ghrelin is a powerful stimulant of appetite in man (Wren A M, Seal L J, Cohen M A, Brynes A E, Frost G S, Murphy K G, Dhillo W S, Ghatei M A, Bloom S R 2001 Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab 86:5992) and preprandial rises in plasma ghrelin have been suggested to be a trigger for meal initiation (Cummings D E, Purnell J Q, Frayo R S, Schmidova K, Wisse B E, Weigle D S 2001 A preprandial rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 50:1714-1719).
  • Intravenous infusion of OXM has been shown to inhibit gastric emptying in humans. Suppression of gastric-emptying may lead to increased gastric distension which may contribute to satiety by causing a sensation of fullness.
  • hunger scores were significantly reduced by OXM in the fasting state when gastric distension is unlikely to be important. Hence the reduction in appetite in the pre-meal period is unlikely to result from effects of OXM on gastric emptying.
  • the anorectic effect of OXM does not appear to be mediated by stimulation of the release of PYY or leptin as concentrations of these hormones were unaffected by OXM infusion.
  • OXM may contribute to the loss of appetite and weight loss observed in these conditions.
  • lower postprandial concentrations of OXM contribute to the physiological reduction of appetite in normal individuals and that exogenous administration of OXM has potential to reduce food intake and/or increase energy expenditure in the obese.
  • OXM is potentially important in both long and short-term regulation of food intake, energy expenditure and body weight maintenance. Therefore, OXM may be useful in the treatment or prevention of excess weight such as obesity in mammals, and further represents a target for the development of therapeutic agents in the treatment of excess weight such as obesity in mammals, especially humans.

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