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WO2004052368A1 - Use of certain compounds in treatment of obesity - Google Patents

Use of certain compounds in treatment of obesity Download PDF

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Publication number
WO2004052368A1
WO2004052368A1 PCT/SE2003/001913 SE0301913W WO2004052368A1 WO 2004052368 A1 WO2004052368 A1 WO 2004052368A1 SE 0301913 W SE0301913 W SE 0301913W WO 2004052368 A1 WO2004052368 A1 WO 2004052368A1
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WO
WIPO (PCT)
Prior art keywords
active compound
obesity
pharmaceutically active
interleukin
use according
Prior art date
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Ceased
Application number
PCT/SE2003/001913
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French (fr)
Inventor
Claes Ohlsson
John-Olov Jansson
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Endocrine Health I Goteborg AB
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Endocrine Health I Goteborg AB
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Filing date
Publication date
Priority claimed from SE0203642A external-priority patent/SE526153C2/en
Application filed by Endocrine Health I Goteborg AB filed Critical Endocrine Health I Goteborg AB
Priority to AU2003283938A priority Critical patent/AU2003283938A1/en
Publication of WO2004052368A1 publication Critical patent/WO2004052368A1/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2026—IL-4
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • A61K38/2086—IL-13 to IL-16
    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A61K38/212—IFN-alpha
    • 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

Definitions

  • the present invention relates to the use of certain compounds in the manufacture of pharmaceutical preparations and a new method for treatment of obesity, in particular pathological disturbances of regulation of body fat tissue mass and/or obesity associ- ated disorders, such as visceral obesity.
  • the metabolic syndrome is the metabolic syndrome
  • alcohol also enhances visceral obesity and increased serum triglyceride levels, i.e., manifestations of the metabolic syndrome.
  • Obesity is a large problem in the Western world since both severe and moderate obesity is associated with increased health risks.
  • Obesity is associated with diseases such as diabetes, hypertension and heart disease, whose incidence increases with body-mass index (BMI, body mass in kg/square of height in meters).
  • BMI body-mass index
  • a study based on information on 18-year-old Swedish military conscripts show a 1.4-fold increase in prevalence of overweight (BMI >25) and a 1.7-fold increase in obesity (BMI >30) from the year 1971 to 1993 (Rasmussen F, Johansson M and Hansen HO, 1999).
  • obesity is due to energy intake that greater than energy expenditure. This can be caused by overeating, i.e. higher food intake than necessary for maintenance of body mass.
  • low mobility and low metabolic rate may predispose for obesity (see Flier, J. S. and Foster D. W. (1998) Eating disorders: obesity, anorexia nervosa, and bulimia nervosa. In: Williams Textbook of Endocrinology, 9th Ed, Saunders Co.).
  • mice can be used for investigating which genes that are causing development of obesity. Of particular importance is the information that can be gained from mouse strains that develop obesity because of gene knockouts. These mouse strains can provide evidence that a certain gene product is of crucial importance for regulation of body fat. This in turn may facilitate the development of new treatment paradigms. There are indications that there are gender differences regarding the genetic ethiology of obesity (see e.g. Costet, P. et al. (1998) Peroxisome Proliferator-activated receptor ⁇ -isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steato- sis. J. Biochem. Chem. 273,29577-29585).
  • hypothalamohypophy- seal and endocrine disturbances, focusing on the effects of the hypothalamus-pituitary- adrenal (HPA) axis regulating glucocorticoid, sex steroids and growth hormone (see e.g. Bjorntorp, P. (1996) The regulation of adipose tissue distribution in humans, Int. J. Obesity 20, 291-301.) Obesity and obesity-related disorders are thus among the leading causes of illness and mortality in the developed world (Kopelman PG, 2000, "Obesity as a medical problem", Nature 404: 635-43), Parts of the brain, including specific regions of the hypothalamus and the brain stem, are involved in the regulation of feeding and body fat mass
  • the aim of the present invention is to provide new medical products and methods for treatment of obesity.
  • the invention relates to the use of certain substances for the production of a pharmaceutical preparation that upon administration to a patient reduces adipose tissue mass for treatment of obesity, in particular visceral obesity.
  • the invention relates to a method for treatment of obesity wherein a pharmaceutically effective amount of a certain substance that upon administration to a patient for reducing adipose tissue mass.
  • statins in particular atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, and interferon alpha-2b or a "functionally equivalent analogue" selectively can decrease body fat.
  • interelukin-4 IL-4
  • interleukin-13 IL-13
  • IL-4, IL-13 and other IL-4 receptor agonists are used to treat obesity and obesity related diseases.
  • the invention thus relates to medicinal products comprising a substance that upon administration to a patient leads to reduced obesity.
  • the expression "functionally equivalent analogue” used herein relates to any substance that is structurally similar to the compounds of the group given above and has essentially the same pharmacological and/or therapeutical effects.
  • patient used herein relates to any human or non-human mammal in need of treatment with the pharmaceutical preparation or method according to the invention.
  • Patients particularly suitable for treatment according to the invention are patients suffering from the metabolic syndrome.
  • treatment used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition.
  • chronic treatment is meant treatment that continues for more than two weeks.
  • the medicinal product and the method according to the invention are suitable for treatment of different pathological disturbances of regulation of body adipose tissues. More precisely, the medicinal product and the method according to the invention are suitable for treatment of obesity and overweight by reducing adipose tissue mass.
  • Obesity includes visceral or general obesity that is due to genetic predisposition, a condition sometimes described as the thrifty genotype.
  • the medicinal product and the method according to the invention could also be used to enhance the effects of exercise and/or diet.
  • Obesity is often associated with resistance to leptin treatment.
  • Visceral obesity includes obesity in the abdominal cavity, in and around the liver, as well as abdominal muscle fat.
  • the reduction in adipose tissue mass according to the invention preferably results in a weight reduction that is larger than 3%, preferably larger than 5% of the body weight at the start of treatment.
  • statin fluvastatin a so called statin, a group of substances known to inhibit HMG Co A reductase.
  • the worms do not have visceral and subcutaneous fat cells in a similar way as higher organisms. Instead they store fat droplets in intestinal cells and hypo- dermal cells. As the worm is transparent the fat can easily be visualised with Nile Red fat staining as shown in the attached FIG. 1, wherein the left image shows the C. elegans control, i.e., a situation prior to treatment with fluvastatin, and the right image shows the result after treatment with fluvastatin.
  • the medicinal product or pharmaceutical composition or pharmaceutical preparation according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art.
  • Said substance according to the invention is preferably formulated in a form enabling passage of the certain compound of the group given.
  • Said substance can be administered subcutaneously, intramuscularly, intravenously, intraperitoneally, intranasally or orally.
  • the substance according to the invention is preferably administered in a dose of 0.1 mg to 200 mg per kg body weight per day or alternatively 5 000 to 500 000 International Units per kg body weight per day.
  • the invention relates to a method for chronic treatment of obesity wherein a pharmaceutically effective amount of a compound of the group given that upon administration to a patient is administered to said patient for reducing adipose tissue mass.
  • a "pharmaceutically active amount" of the substance is used.
  • This expression relates to a dose of the substance that will lead to the desired pharmacological and/or therapeutic effect.
  • the desired pharmacological and/or therapeutic effect is, as stated above, to cure or alleviate different pathological disturbances of regulation of body adipose tissues, leading to obesity, i.e. treatment of obesity and overweight by reducing adipose tissue mass.
  • the compounds of the present invention can be administered in the form of oral, rectal, injection, or inhalation preparations.
  • Oral compositions normally exist as tablets, granules, capsules (soft or hard), or powders, either coated or uncoated products.
  • coated products they may be merely enteric coated to provide for a more readily administered preparation, or as a sustained release coated composition, where the release of active compound will take place due to the dissolution of the coating, which dissolution is dependent on where in the gastro-intestinal tract one will have a release.
  • the release can be controlled as to place and time. It may also be advantageous to coat the active compound if this is subject to degradation, such as by gastric acid, in order then to have the compound to pass the stomach.
  • Tablets and capsules normally contain one dose of the active compound, i.e., the dose determined to fulfil the requirements of obtaining a therapeutically active level in serum or otherwise, either this is required once, twice or more times a day (24 hrs).
  • Rectal compositions are normally prepared as suppositories, where the active compound is dissolved or dispersed in a waxy compound or fat having a melting temperature in the range of the body temperature, as to release the active compound when administered rectally.
  • Preparations for injection are commonly made for subcutaneous, intramuscular, intravenous, or intra peritoneal administration.
  • Injection solutions are normally provided with an adjuvant to facilitate absorption of the active compound.
  • Preparations for inhalation are commonly present as powders which are administered either in pressurized containers with a dosing nozzle, or in an inhaler system where the powder is dosed in the system and then the patient is inhaling air through the apparatus to such degree that the powder becomes airborne and enters the respiratory tract, including the lungs.
  • Inhalation preparation are normally used for inflammatory conditions in the respiratory tract including the lungs.
  • compositions contain 0.5 to 99 % by weight of active compound, and the remainder is different inert, non-therapeutically active compounds which facilitate administration, preparation such as granulation, tableting, or storage.
  • inert materials may, however, have a administratively positive effect.
  • the active compounds of the invention is administered in an amount of 0.1 to 200 mg or 5 000 to 500 000 International Units per kilogram body weight depending on the condition of the patient, route of administration, age and body weight of the patient, and other considerations made by the physician.
  • the most important aspect hereby is the serum concentration which may be 0.1 to 100 mM of active compound, in accordance with present findings.
  • the treatment according to the invention with other conventional pharmacological treatments of obesity.
  • the substance according to the invention may thus be administered in combination with other conventional pharmaceuticals used to treat obesity.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Child & Adolescent Psychology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of one or more compound selected from the group of statins, in particular rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, interferone alpha-2b, interleukin-4 (IL-4), interleukin-13 (IL-13) and other interleukin-4 receptor agonists, or a functionally equivalent analogue in the manufacture of pharmaceutical preparations for the treatment of obesity, as well as a method for treatment of obesity.

Description

TITLE
USE OF CERTAIN COMPOUNDS IN TREATMENT OF OBESITY
DESCRIPTION
Technical field of the invention
The present invention relates to the use of certain compounds in the manufacture of pharmaceutical preparations and a new method for treatment of obesity, in particular pathological disturbances of regulation of body fat tissue mass and/or obesity associ- ated disorders, such as visceral obesity.
Background art
The metabolic syndrome
It is well recognized that visceral obesity, deranged lipid-lipoprotein profile, including hypertriglyceridemia, hypertension, and insulin resistance are related in a group of metabolic perturbations called the metabolic syndrome. This syndrom is associated with larger risk of cardiovascular disease. So far, a lot of the research on the ethiology of this syndrome has concentrated on neuroendocrine, i.e., hypothalmic, and endocrine distur- bancies, focusing on the effects of the HPA axis, sex steroids and growth hormone, as well as, of course, insulin (Bjorntorp, P. Body fat distribution, insulin resistance, and metabolic diseases. Nutrition 13, 795-803 (1997). review).
The risk for abdominal obesity and the metabolic syndrome seem to genetically determined to a large extent. According to the thrifty gene hypothesis, genetic selection would favor storage of fat ensure large energy supplies during times of starvation. For several years, several research groups throughout the world have tried to identify thrifty genes. Some of the candidate genes have been detected after identification of genetically obese mouse models (Friedman JM and Halaas JL, Leptin and the regulation of body weight in mammals. Nature 395, 763-70, 1998 ).
Under certain circumstances, alcohol also enhances visceral obesity and increased serum triglyceride levels, i.e., manifestations of the metabolic syndrome.
Understanding obesity
Obesity is a large problem in the Western world since both severe and moderate obesity is associated with increased health risks. Obesity is associated with diseases such as diabetes, hypertension and heart disease, whose incidence increases with body-mass index (BMI, body mass in kg/square of height in meters). A study based on information on 18-year-old Swedish military conscripts show a 1.4-fold increase in prevalence of overweight (BMI >25) and a 1.7-fold increase in obesity (BMI >30) from the year 1971 to 1993 (Rasmussen F, Johansson M and Hansen HO, 1999).
Generally, obesity is due to energy intake that greater than energy expenditure. This can be caused by overeating, i.e. higher food intake than necessary for maintenance of body mass. In addition, low mobility and low metabolic rate may predispose for obesity (see Flier, J. S. and Foster D. W. (1998) Eating disorders: obesity, anorexia nervosa, and bulimia nervosa. In: Williams Textbook of Endocrinology, 9th Ed, Saunders Co.).
However, the general opinion that obesity is largely the result of a lack of willpower is unsatisfactory. Intense research efforts are therefore made to reveal the genetic and environmental factors of importance for development of obesity (Friedman JM and Ha- laas JL, 1998).
Obesity in humans and mice
Animal models can be used for investigating which genes that are causing development of obesity. Of particular importance is the information that can be gained from mouse strains that develop obesity because of gene knockouts. These mouse strains can provide evidence that a certain gene product is of crucial importance for regulation of body fat. This in turn may facilitate the development of new treatment paradigms. There are indications that there are gender differences regarding the genetic ethiology of obesity (see e.g. Costet, P. et al. (1998) Peroxisome Proliferator-activated receptor α-isoform deficiency leads to progressive dyslipidemia with sexually dimorphic obesity and steato- sis. J. Biochem. Chem. 273,29577-29585).
Obesity and blood fats in relation to cardiovascular disease
It is recognized that obesity, especially visceral obesity, and deranged lipid-lipoprotein profile, including hypertriglyceridemia and hypercholesterolemia are associated with larger risk of cardiovascular disease (Lamarche B, et al. (1998), Visceral obesity and the risk of ischemic heart disease: insights from the Quebec cardiovascular study. Growth hormone and IGF research 8, (suppl. B) 1-8.). So far, a lot of the research on the ethiology of this syndrome has dealt with neuroendocrine, i.e. hypothalamohypophy- seal, and endocrine disturbances, focusing on the effects of the hypothalamus-pituitary- adrenal (HPA) axis regulating glucocorticoid, sex steroids and growth hormone (see e.g. Bjorntorp, P. (1996) The regulation of adipose tissue distribution in humans, Int. J. Obesity 20, 291-301.) Obesity and obesity-related disorders are thus among the leading causes of illness and mortality in the developed world (Kopelman PG, 2000, "Obesity as a medical problem", Nature 404: 635-43), Parts of the brain, including specific regions of the hypothalamus and the brain stem, are involved in the regulation of feeding and body fat mass
(Friedman JM, Halaas JL, 1998, "Leptin and the regulation of body weight in mammals", Nature 395: 763-70; Schwartz MW, Woods SC, Porte D Jr, Seeley P , Baskin DG, 2000, "Central nervous system control of food intake", Nature Apr 6; 404 (6778): 661-71). The regulation of feeding and body mass by the hypothalamus is influenced e.g. by the adipose tissue derived hormone leptin.
Summary of the invention
The aim of the present invention is to provide new medical products and methods for treatment of obesity.
More precisely, the invention relates to the use of certain substances for the production of a pharmaceutical preparation that upon administration to a patient reduces adipose tissue mass for treatment of obesity, in particular visceral obesity.
Furthermore, the invention relates to a method for treatment of obesity wherein a pharmaceutically effective amount of a certain substance that upon administration to a patient for reducing adipose tissue mass.
Detailed description of the invention In the research work leading to the present invention it was found that treatment with one or more of the compounds selected from the group consisting of statins, in particular atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, and interferon alpha-2b or a "functionally equivalent analogue" selectively can decrease body fat.
Further, it has been observed that interelukin-4 (IL-4) and interleukin-13 (IL-13), i e two interleukins that act on IL-4 receptors, will decrease body fat mass.
Based on this finding, it is proposed that IL-4, IL-13 and other IL-4 receptor agonists are used to treat obesity and obesity related diseases.
The invention thus relates to medicinal products comprising a substance that upon administration to a patient leads to reduced obesity. The expression "functionally equivalent analogue" used herein relates to any substance that is structurally similar to the compounds of the group given above and has essentially the same pharmacological and/or therapeutical effects.
The term "patient" used herein relates to any human or non-human mammal in need of treatment with the pharmaceutical preparation or method according to the invention.
Patients particularly suitable for treatment according to the invention are patients suffering from the metabolic syndrome.
The term "treatment" used herein relates to both treatment in order to cure or alleviate a disease or a condition, and to treatment in order to prevent the development of a disease or a condition. By "chronic treatment" is meant treatment that continues for more than two weeks.
The medicinal product and the method according to the invention are suitable for treatment of different pathological disturbances of regulation of body adipose tissues. More precisely, the medicinal product and the method according to the invention are suitable for treatment of obesity and overweight by reducing adipose tissue mass.
Obesity includes visceral or general obesity that is due to genetic predisposition, a condition sometimes described as the thrifty genotype. Obesity caused by lifestyle and environment, such as lack of exercise, or diets with high caloric content or high fat content, can also be treated as described herein. The medicinal product and the method according to the invention could also be used to enhance the effects of exercise and/or diet. Obesity is often associated with resistance to leptin treatment. Visceral obesity includes obesity in the abdominal cavity, in and around the liver, as well as abdominal muscle fat.
The reduction in adipose tissue mass according to the invention preferably results in a weight reduction that is larger than 3%, preferably larger than 5% of the body weight at the start of treatment.
Experimental In order to show the fat reducing effect of statins the following experiment was carried out.
Addition of 1 mM of fluvastin suppresses fat content in the worm C. elegans. The statin fluvastatin was added to the medium of an agar plate with C. elegans, and the fat con- tent of intestinal cells was found to be reduced in the worm, presumably after it has ingested the fluvastatin, a so called statin, a group of substances known to inhibit HMG Co A reductase. The worms do not have visceral and subcutaneous fat cells in a similar way as higher organisms. Instead they store fat droplets in intestinal cells and hypo- dermal cells. As the worm is transparent the fat can easily be visualised with Nile Red fat staining as shown in the attached FIG. 1, wherein the left image shows the C. elegans control, i.e., a situation prior to treatment with fluvastatin, and the right image shows the result after treatment with fluvastatin.
The medicinal product or pharmaceutical composition or pharmaceutical preparation according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art.
Said substance according to the invention is preferably formulated in a form enabling passage of the certain compound of the group given.
Said substance can be administered subcutaneously, intramuscularly, intravenously, intraperitoneally, intranasally or orally.
The substance according to the invention is preferably administered in a dose of 0.1 mg to 200 mg per kg body weight per day or alternatively 5 000 to 500 000 International Units per kg body weight per day.
Furthermore, the invention relates to a method for chronic treatment of obesity wherein a pharmaceutically effective amount of a compound of the group given that upon administration to a patient is administered to said patient for reducing adipose tissue mass.
In the method according to the present invention, a "pharmaceutically active amount" of the substance is used. This expression relates to a dose of the substance that will lead to the desired pharmacological and/or therapeutic effect. The desired pharmacological and/or therapeutic effect is, as stated above, to cure or alleviate different pathological disturbances of regulation of body adipose tissues, leading to obesity, i.e. treatment of obesity and overweight by reducing adipose tissue mass.
The compounds of the present invention can be administered in the form of oral, rectal, injection, or inhalation preparations. Oral compositions normally exist as tablets, granules, capsules (soft or hard), or powders, either coated or uncoated products. As coated products they may be merely enteric coated to provide for a more readily administered preparation, or as a sustained release coated composition, where the release of active compound will take place due to the dissolution of the coating, which dissolution is dependent on where in the gastro-intestinal tract one will have a release. Thus the release can be controlled as to place and time. It may also be advantageous to coat the active compound if this is subject to degradation, such as by gastric acid, in order then to have the compound to pass the stomach.
Tablets and capsules normally contain one dose of the active compound, i.e., the dose determined to fulfil the requirements of obtaining a therapeutically active level in serum or otherwise, either this is required once, twice or more times a day (24 hrs).
Rectal compositions are normally prepared as suppositories, where the active compound is dissolved or dispersed in a waxy compound or fat having a melting temperature in the range of the body temperature, as to release the active compound when administered rectally.
Preparations for injection are commonly made for subcutaneous, intramuscular, intravenous, or intra peritoneal administration. Injection solutions are normally provided with an adjuvant to facilitate absorption of the active compound.
Preparations for inhalation are commonly present as powders which are administered either in pressurized containers with a dosing nozzle, or in an inhaler system where the powder is dosed in the system and then the patient is inhaling air through the apparatus to such degree that the powder becomes airborne and enters the respiratory tract, including the lungs. Inhalation preparation are normally used for inflammatory conditions in the respiratory tract including the lungs.
The compositions contain 0.5 to 99 % by weight of active compound, and the remainder is different inert, non-therapeutically active compounds which facilitate administration, preparation such as granulation, tableting, or storage. Such inert materials may, however, have a administratively positive effect.
The active compounds of the invention is administered in an amount of 0.1 to 200 mg or 5 000 to 500 000 International Units per kilogram body weight depending on the condition of the patient, route of administration, age and body weight of the patient, and other considerations made by the physician. The most important aspect hereby is the serum concentration which may be 0.1 to 100 mM of active compound, in accordance with present findings.
Furthermore, it is possible to combine the treatment according to the invention with other conventional pharmacological treatments of obesity. The substance according to the invention may thus be administered in combination with other conventional pharmaceuticals used to treat obesity.

Claims

1. Use of one or more of the compounds selected from the group consisting of statins, in particular rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, interferon alpha-2b, interleukin-4 (IL-4), interleukin-13 (IL-13) and other interleukin-4 (IL-4) receptor agonists, or a "functionally equivalent analogue" in the manufacture of a pharmaceutical preparation for the treatment of obesity.
2. Use according to claim 1, wherein the pharmaceutically active compound is selected from the group of statins.
3. Use according to claim 1, wherein the pharmaceutically active compound is atorvastatin.
4. Use according to claim 1, wherein the pharmaceutically active compound is simvastatin.
5. Use according to claim 1, wherein the pharmaceutically active compound is fluvastatin.
6. Use according to claim 1, wherein the pharmaceutically active compound is pravastatin.
7 Use according to claim 1, wherein the pharmaceutically active compound is rosuvastatin.
8. Use according to claim 1, wherein the pharmaceutically active compound is terbinafine.
9. Use according to claim 1, wherein the pharmaceutically active compound is interferon alpha-2b.
10. A method according to claim 1, wherein the pharmaceutically active compound is IL-4.
11. Use according to claim 1, wherein the pharmaceutically active compound is IL-13
12. Use according to claim 1, wherein the pharmaceutically active compound is an IL-4 receptor agonist other than IL-4 and IL-13.
13. Use according to claims 1-12, wherein the pharmaceutically active compound is a functionally equivalent analogue thereof.
14. Use according to claim 1, wherein said obesity is visceral or general obesity that is due to genetic predisposition.
15. Use according to claim 1, wherein said obesity is caused by lifestyle or environment.
16. Use according to claim 1, wherein said obesity is a symthom of the metabolic syndrome.
17. Use for chronic treatment of obesity wherein a pharmaceutically effective amount of one or more of the compounds selected from the group consisting of statins, in particular rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, interferon alpha-2b, interleukin-4 (IL-4), interleukin-13 (IL-13) and other interleukin-4 (IL-4) receptor agonists, or a "functionally equivalent analogue" thereof is administered to said patient for reducing adipose tissue mass.
18. A method for treatment of obesity wherein a pharmaceutically effective amount of one or more of the compounds selected from the group consisting of statins, in particular rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, interferon alpha-2b, and interleukin-4 (IL-4), interleukin-13 (IL-13) and other interleukin-4 (IL-4) receptor agonists, or a "functionally equivalent analogue" thereof is administered to said patient for reducing adipose tissue mass.
19. A method according to claim 18, wherein the pharmaceutically active compound is selected from the group of statins.
20. A method according to claim 18, wherein the pharmaceutically active compound is atorvastatin.
21. A method according to claim 18, wherein the pharmaceutically active compound is simvastatin.
22. A method according to claim 18, wherein the pharmaceutically active compound is fluvastatin.
23. A method according to claim 18, wherein the pharmaceutically active compound is pravastatin.
24. A method according to claim 18, wherein the pharmaceutically active compound is rosuvastatin.
25. A method according to claim 18, wherein the pharmaceutically active compound is terbinafine.
26. A method according to claim 18, wherein the pharmaceutically active compound is interferon alpha-2b.
27. A method according to claim 18, wherein the pharmaceutically active compound is IL-4.
28. A method according to claim 18, wherein the pharmaceutically active compound is IL-13
29. A method according to claim 18, wherein the pharmaceutically active compound is an IL-4 receptor agonist other than IL-4 and IL-13.
30. A method according to claims 18-29, wherein the pharmaceutically active compound is a functionally equivalent analogue thereof.
31. A method according to claim 18, wherein said obesity is visceral or general obesity that is due to genetic predisposition.
32. A method according to claim 18, wherein said obesity is caused by lifestyle or environment.
33. A method for chronic treatment of obesity wherein a pharmaceutically effective amount of one or more of the compounds selected from the group consisting of statins, in particular rosuvastatin, atorvastatin, simvastatin, fluvastatin, pravastatin, and terbinafine, interferon alpha-2b, interleukin-4 (IL-4), interleukin-13 (IL-13) and other interleukin-4 (IL-4) receptor agonists, or a "functionally equivalent analogue" thereof is administered to said patient for reducing adipose tissue mass.
PCT/SE2003/001913 2002-12-06 2003-12-08 Use of certain compounds in treatment of obesity Ceased WO2004052368A1 (en)

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EP1621210A4 (en) * 2003-04-28 2009-08-05 Sankyo Co ACTIVATOR OF ADIPONECTIN PRODUCTION
US7772272B2 (en) 2003-04-28 2010-08-10 Daiichi Sankyo Company, Limited Method for enhancing glucose uptake into warm-blooded animal adipocytes
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US8105842B2 (en) 2005-02-21 2012-01-31 Saga University Interleukin-13 as a cardiovascular disease marker
EP1861490A4 (en) * 2005-03-23 2010-11-17 Univ St Louis USE OF ARCHAEA FOR MODULATING NUTRITIONAL FUNCTIONALITY OF GASTROINTESTINAL BIOZOOSIS
FR2987270A1 (en) * 2012-02-29 2013-08-30 Agronomique Inst Nat Rech COMBINATION PRODUCT FOR TREATING OVERWEIGHT AND / OR IMPROVING SILHOUETTE
WO2013128137A1 (en) * 2012-02-29 2013-09-06 Institut National De La Recherche Agronomique - Inra Combination product for treating excess weight and/or for improving the figure
WO2017059389A1 (en) * 2015-10-01 2017-04-06 Kythera Biopharmaceuticals, Inc. Compositions comprising a statin for use in methods of adipolysis
US9925170B2 (en) 2015-10-01 2018-03-27 Kythera Biopharmaceuticals, Inc. Methods of adipolysis and compositions useful therein

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