WO1994027629A1 - Procede de maitrise de l'appetit et de traitement de l'obesite - Google Patents

Procede de maitrise de l'appetit et de traitement de l'obesite Download PDF

Info

Publication number
WO1994027629A1
WO1994027629A1 PCT/US1994/005177 US9405177W WO9427629A1 WO 1994027629 A1 WO1994027629 A1 WO 1994027629A1 US 9405177 W US9405177 W US 9405177W WO 9427629 A1 WO9427629 A1 WO 9427629A1
Authority
WO
WIPO (PCT)
Prior art keywords
human
patient
apolipoprotein
human apolipoprotein
active fragment
Prior art date
Application number
PCT/US1994/005177
Other languages
English (en)
Inventor
Jonathan A. Tobert
Original Assignee
Merck & Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Merck & Co., Inc. filed Critical Merck & Co., Inc.
Priority to AU72423/94A priority Critical patent/AU7242394A/en
Publication of WO1994027629A1 publication Critical patent/WO1994027629A1/fr

Links

Classifications

    • 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
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals

Definitions

  • the present invention relates to the administration of human apolipoprotein A-IV, isoforms and active fragments thereof, to humans as an injectable formulation for the purpose of controlling appetite and reducing food intake and body weight.
  • the invention is also directed to an injectable pharmaceutical formulation of human apolipoprotein A-IV, or active fragments thereof.
  • Obesity is a ubiquitous problem in industrialized countries and can produce major medical and psychosocial liabilities. Obesity is a difficult medical problem because there are no adequate methods available for long term appetite control. Dietary therapy generally fails to produce sustained weight loss and the available drugs-sympatheo- mimetic amines and agents increasing brain serotonin levels— are not currently indicated in the United States for long-term treatment of obesity. Consequently, the treatment of obesity generally meets with limited success. Eating behavior is difficut to modify, except by surgical means. Patients with severe obesity sometimes undergo surgical procedures such as jaw wiring and gastric stapling to control their appetite and reduce their weight. The present invention fulfills the need for a safe and effective non-surgical treatment of obesity.
  • a problem related to obesity is bulimia nervosa, a behavioral disease characterized by excessive "binge” eating followed by vomiting or other purging behavior.
  • the method of the present invention controls appetite and may be useful in the treatment of bulimia nervosa.
  • each individual has a barometric "set point", i.e., a body weight he or she will maintain over long periods of time if food supplies are adequate.
  • the set point is determined by genetic, familial and cutural factors.
  • body weight is determined mainly by eating behavior, with other factors such as basal metabolic rate and energy expenditure by exercise playing a more minor role.
  • Experiments on parabiotic rodents have suggested the existence of one or more long-acting circulating satiety factors, which suppress appetite and consequently food intake.
  • apolipoprotein A-IV The function of this apolipoprotein of molecular weight about 45,000 was previously undefined. It is known to be secreted by the small intenstine following the ingestion of fat and is probably catabolized by the liver. Unlike other apolipoproteins, a large fraction of circulating apolipoprotein A-IV is lipoprotein-free or only loosely associated with lipoproteins, making it potentially transportable across the blood brain barrier.
  • the plasma half life of human apolipoprotein A-IV is several hours.
  • the level of this glycoprotein in blood is determined by secretion by the gut, which is known to be ultimately be mitmulated by ingestion of fat, and probably by catabolism by the liver. Little is known about the latter; it is known that apolipo ⁇ protein A-IV binds to hepatocellular membranes and thus is probably taken up and metabolized by the liver. It is likely that the liver, as the central organ of metabolism, plays a major role in the control of body weight, including bringing an organism to its "set point.”
  • An isoform is a genetically determined variant of a protein. Depending on the population examined, the allele frequency of human apolipoprotein A-IV-1, the primary isoform, is about 94%; for apolipoprotein A-IV -2, the second most prevalent isoform, the allele frequency is about 6%.
  • Apolipoprotein A-IV-3 and A-IV -4 are the other identified isoforms; the allele frequency for these isoforms is very low. See Menzel et ah, J. Lipid Res. 23: 915-922 (1990) and Lohse et al.. J. Biol. Chem. 265: 12734-12739 (1990).
  • apolipoprotein A-IV may be a long acting satiety factor in rats; they show that apolipoprotein A-IV concentrations in cerebrospinal fluid increase during feeding, that infusion of apolipoprotein A-IV into the third ventricle inhibits food intake in fasted animals and that feeding behavior can be stimulated by antibodies to apolipoprotein A-IV infused into the third ventricle.
  • the present invention surprisingly provides that human apolipoprotein A-IV, isoforms thereof and active fragments thereof, can be used to control appetite in humans. No apolipoproteins or lipoproteins have been used for any accepted therapeutic purpose to date.
  • the present invention relates to the administration of human apolipoprotein A-IV, and active fragments thereof, to humans as injectable formulations for the purpose of controlling appetite and reducing food intake and body weight, and controlling obesity and bulimia.
  • the invention is also directed to an injectable pharmaceutical formulation of human apolipoprotein A-IV or an active fragment thereof and an autoinjection device for administration of human apolipoprotein A-IV and active fragments thereof.
  • the present invention relates to administration of human apolipoprotein A-IV, isoforms and active fragments thereof, to humans as an injectable formulation, preferably a subcutaneous formulation, for the purpose of controlling appetite and reducing food intake and body weight.
  • Human apolipoprotein A-IV is a 47 kD glycoprotein which is secreted by the intestine in chylomicrons and, unlike other apolipoproteins, circulates partly free and partly loosely associated with high density lipoprotein. Its regulation and function are largely obscure.
  • Human apolipoprotein A-IV may be produced by recombinant DNA technology and expressed in an expression system such as I coli. However, the entire glycoprotein of molecular weight 47 kD need not be expressed; active fragments of human apolipoprotein A-IV, may also be employed.
  • An active fragment of human apolipoprotein A-IV is defined for purposes of the present invention as an expressed fragment of human apolipoprotein A-IV having appetite suppressant activity.
  • the appetite suppressant activity of a fragment may be measured by intravenous infusion of the fragment of apolipoprotein A-IV over 2 to 8 hours at doses ranging from 10 to 1000 ⁇ g/min. in fasted healthy human volunteers with placebo control.
  • Appetite suppressant activity is measured by a visual analog scale and a questionnaire, and by reduction of consumption of offered standard food items.
  • a fragment that reduces appetite and/or food consumption over the infusion period by 20% or more is an active fragment of apolipoprotein A-IV for the purposes of the present invention.
  • the present invention is also directed to a method of controlling appetite which comprises the administration to a human subject in need of such treatment of a nontoxic therapeutically effective amount of human apolipoprotein A-IV, including isoforms thereof, or an active fragment thereof, by injection.
  • the method of this invention is useful in treating obesity, bulimia nervosa and like diseases in humans for which treatment requires reduction in food intake or suppression of appetite.
  • the human apolipoprotein A-IV, or active fragment thereof may be administered subcutaneously or intramuscularly, preferably subcutaneously since subcutaneous administration causes less patient discomfort. Administration may occur one to four times daily or less frequently at a therapeutically effective dose.
  • the human apolipoprotein A-IV or an active fragment thereof may also be administered on an intermittent basis when therapeutically advisable, e.g. in the treatment of bulimia nervosa.
  • Dosages may be varied, depending on the age, severity of obesity and other conditions of human patients, but daily dosage for adults is within a range of from about 0.1 mg to 2000 mg, preferably 1 mg to 500 mg, which may be given in a single dose or two or more divided dosages. Higher dosages may be favorably employed as required.
  • Human apolipoprotein A-IV, or an active fragment thereof produced by recombinant DNA technology or other means is formulated as an injectable formulation, preferably a subcutaneous injection.
  • the formulation may be formulated as either a suspension or a solution.
  • a suspension may have the advantage of providing more gradual release of the active agent.
  • the suspensions or solutions of the formulation of the present invention contain 0.1% to 15% human apolipoprotein A-IV, preferably 1% to 10%, in a pharmaceutically acceptable carrier.
  • the human apolipoprotein A-IV is administered as an injectable suspension or solution comprising human apolipoprotein A- IV, or an active fragment thereof, and a suitable pharmaceutical carrier.
  • injectable suspensions may be formulated according to known art, using suitable non-toxic, parenterally acceptable diluents or solvents, such as 1 ,2-propanediol, water, Ringer's solution, dextrose solution or isotonic sodium chloride solution.
  • injectable suspensions or solutions may further contain excipients suitable for manufacture of aqueous suspensions and solutions. Such excipients may be:
  • suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;
  • suspensions and solutions may further contain microcrystalline cellulose for imparting bulk and methylcellulose as a viscosity enhancer.
  • aqueous suspensions and solutions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxy- benzoate, and antioxidants and the like may be incorporated as required.
  • preservatives for example, ethyl or n-propyl p-hydroxy- benzoate, and antioxidants and the like may be incorporated as required.
  • aqueous suspension or solution may, if necessary, be buffered to a physiologically appropriate pH by the addition of a suitable buffer such as sodium acetate, sodium lactate, sodium benzoate or Tris.
  • a suitable buffer such as sodium acetate, sodium lactate, sodium benzoate or Tris.
  • Dispersible powders and granules are suitable for the preparation of an aqueous suspension. They provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present.
  • An oily suspension may be formulated by suspending the active ingredient in a vegetable oil, for example: arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example: beeswax, hard paraffin or cetyl alcohol.
  • These compositions may be prepared by the addition of an antioxidant such as ascorbic acid.
  • human apolipoprotein be formulated in a suspension.
  • compositions of the suspensions and solutions of human apolipoprotein A-IV, and active fragments thereof, of the present invention when administered by intramuscular or subcutaneous injection avoid the inconvenience of intravenous administration while maintaining the advantages of parenteral administration, i.e,, good bioavailability.
  • This treatment although it requires an injection, is likely be accepted by patients with moderate to severe obesity. (Surgical procedures such as jaw wiring and gastric stapling are currently employed in some severely obese patients.)
  • the formulation of the present invention may be used in conjunction with modern auto-injection devices which increases the convenience and decreases the discomfort of subcutaneous injections.
  • the use of the formulation of the present invention with such autoinjection devices may increase patient compliance by improving ease of administration.
  • the formulation is filtered to remove organisms and dispensed into a 2 mL glass vial.
  • the present experiment involved assaying apolipoprotein A-IV in archived specimens from the above-described study, using a sandwich ELISA method.
  • Table 1 Mean (95% C.I.) values of apolipoprotein A-IV and body weight at the end of the 9 week periods, with corresponding values for reported dietary energy and fat content.
  • lovastatin had no effect on plasma apolipoprotein A-IV, but the low-fat diet produced a substantial and significant decrease.
  • the differences in dietary composition are probably overestimated, as suggested by the modest changes in weight (as well as lipids).
  • Figure 1 shows the relative composition and effects of the low- fat diet on all the apolipoproteins measured. Since there was no evidence for an interaction between the dietary and drug interventions for apolipoprotein A-IV or any other apolipoprotein, the overall percent difference in the mean for the low fat diet compared to the high fat diet are shown. (Similar results were obtained when the lovastatin periods were excluded.)
  • Figure 1 Percent Difference In Mean Apolipoprotein Levels, Low Fat Versus High Fat Diet. Error bars represent 95% C.I.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne l'administration d'une apolipoprotéine humaine A-IV, d'isoformes et de fragments actifs de celle-ci, à des individus sous la forme d'une formulation injectable afin de maîtriser l'appétit ainsi que de réduire la ration alimentaire et le poids du coprs. L'invention concerne également une formulation pharmaceutique injectable d'apolipoprotéine A-IV humaine, ou de fragments actifs de celle-ci.
PCT/US1994/005177 1993-05-28 1994-05-10 Procede de maitrise de l'appetit et de traitement de l'obesite WO1994027629A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU72423/94A AU7242394A (en) 1993-05-28 1994-05-10 Method to control appetite and treat obesity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7069093A 1993-05-28 1993-05-28
US070,690 1993-05-28

Publications (1)

Publication Number Publication Date
WO1994027629A1 true WO1994027629A1 (fr) 1994-12-08

Family

ID=22096818

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/005177 WO1994027629A1 (fr) 1993-05-28 1994-05-10 Procede de maitrise de l'appetit et de traitement de l'obesite

Country Status (2)

Country Link
AU (1) AU7242394A (fr)
WO (1) WO1994027629A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025749A2 (fr) * 1994-03-22 1995-09-28 Research Corporation Technologies, Inc. Peptides coupe-faim
WO2004084800A2 (fr) * 2002-08-29 2004-10-07 Pfizer Products Inc. Proteines cardioprotectrices a mediation du recepteur a3, leurs methodes therapeutiques et diagnostiques d'utilisation
US9051394B2 (en) 2011-01-19 2015-06-09 University Of Cincinnati Apolipoprotein AIV as an antidiabetic peptide
US9730980B2 (en) 2012-07-25 2017-08-15 University Of Cincinnati Method of treating type I diabetes using apolipoprotein A-IV
US9951120B2 (en) 2012-01-19 2018-04-24 University Of Cincinnati Method of treating diabetes using non-glycosylated apolipoprotein A-IV
US10232019B2 (en) 2012-07-25 2019-03-19 University Of Cincinnati Method of treating hyperglycemic disorders using apolipoprotein AIV

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5013722A (en) * 1986-06-06 1991-05-07 Hoffmann-Laroche Inc. Cholecystokinin analogs for controlling appetite

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5013722A (en) * 1986-06-06 1991-05-07 Hoffmann-Laroche Inc. Cholecystokinin analogs for controlling appetite

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
AMER. J. PHYSIOL., Volume 262, No. 6 (part 1), issued 1992, KAZUMA FUJIMOTO et al., "Increased Apolipoprotein A-IV in Rat Mesenteric Lymph after Lipid Meal Acts as a Physiological Signal for Satiation", pages G1002-1006. *
BRAIN RES., Volume 608, issued 1993, KAZUMA FUJIMOTO et al., "Effect of Intravenous Administration of Apolipoprotein A-IV on Patterns of Feeding, Drinking and Ambulatory Activity of Rats", pages 233-237. *
J. CLIN. INVEST., Volume 91, issued April 1993, KAZUMA FUJIMOTO et al., "Suppression of Food Intake by Apolipoprotein A-IV is Mediated through the Central Nervous System in Rats", pages 1830-1833. *
JOUR. OF LIPID RES., Volume 25, issued 1984, MICHAEL LEFEVRE et al., "Metabolism of Apolipoprotein A-IV", pages 1603-1610. *
THE UNITED STATES PHARMACOPEIA XXI, issued 1985, pages 1491-1493, 964, 966 and 1103. *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995025749A2 (fr) * 1994-03-22 1995-09-28 Research Corporation Technologies, Inc. Peptides coupe-faim
WO1995025749A3 (fr) * 1994-03-22 1995-12-07 Res Corp Technologies Inc Peptides coupe-faim
US5840688A (en) * 1994-03-22 1998-11-24 Research Corporation Technologies, Inc. Eating suppressant peptides
WO2004084800A2 (fr) * 2002-08-29 2004-10-07 Pfizer Products Inc. Proteines cardioprotectrices a mediation du recepteur a3, leurs methodes therapeutiques et diagnostiques d'utilisation
WO2004084800A3 (fr) * 2002-08-29 2005-10-06 Pfizer Prod Inc Proteines cardioprotectrices a mediation du recepteur a3, leurs methodes therapeutiques et diagnostiques d'utilisation
US9051394B2 (en) 2011-01-19 2015-06-09 University Of Cincinnati Apolipoprotein AIV as an antidiabetic peptide
US9266941B2 (en) 2011-01-19 2016-02-23 University Of Cincinnati Apolipoprotein AIV as an antidiabetic peptide
US9951120B2 (en) 2012-01-19 2018-04-24 University Of Cincinnati Method of treating diabetes using non-glycosylated apolipoprotein A-IV
US9730980B2 (en) 2012-07-25 2017-08-15 University Of Cincinnati Method of treating type I diabetes using apolipoprotein A-IV
US10232019B2 (en) 2012-07-25 2019-03-19 University Of Cincinnati Method of treating hyperglycemic disorders using apolipoprotein AIV

Also Published As

Publication number Publication date
AU7242394A (en) 1994-12-20

Similar Documents

Publication Publication Date Title
ES2227115T5 (es) Utilización de exendinas y sus agonistas para el tratamiento de la hipertrigliceridemia
Smith et al. Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.
ES2307729T3 (es) Modulacion de un perfil lipidico con esteroides y agonistas de ppar alfa.
Washio et al. Alpha tocopherol improves focal glomerulosclerosis in rats with adriamycin-lnduced progressive renal failure
NZ529243A (en) Use of polymethoxylated flavones for treating insulin resistance
AU2002308324A1 (en) Polymethoxylated flavones for treating insulin resistance
Calabresi et al. Recombinant apolipoprotein A-IMilano for the treatment of cardiovascular diseases
Ansell et al. Modifying the anti-inflammatory effects of high-density lipoprotein
WO1994027629A1 (fr) Procede de maitrise de l'appetit et de traitement de l'obesite
Gandotra et al. The role of triglycerides in cardiovascular risk
Inami et al. Effects of statins on circulating oxidized low-density lipoprotein in patients with hypercholesterolemia
KR101695801B1 (ko) 운동 뉴런의 자가 포식 작용 억제를 위한 약학적 조성물 및 이의 용도
JP3790686B2 (ja) 血糖降下剤
JP2812682B2 (ja) コレステロール排泄促進剤及びコレステロール排泄促進飲食物
JP5936707B2 (ja) インターフェロンおよびアンドログラホリドを用いた多発性硬化症のための併用療法
EA002435B1 (ru) Способ снижения уровня липопротеина (а) в сыворотке или в плазме крови млекопитающих
EP4023663A1 (fr) Polypeptide et son utilisation
FI115826B (fi) Terapeuttinen aine rasva-aineenvaihdunnan häiriöön
Oliviera et al. Triglyceride hydrolysis of soy vs fish oil LCT emulsions
CN112076187B (zh) 安卓锭在制备用于预防或治疗非酒精性脂肪肝的药物中的用途
US5290549A (en) Method for reducing atherosclerotic lesions in a mammal
US6333327B2 (en) Method for the treatment of Multiple Sclerosis
KR100783204B1 (ko) 누룩치 추출물을 포함하는 항비만 또는 항고지혈증 조성물
KR20070015114A (ko) 3,3,14,14 테트라메틸 헥사데칸 1,16 이산의 투여 방법
Nai et al. Comparison of the effectiveness of physical training and extract of soursop leaf to histopathology of abdominal aorta foam cells in hipercolesterolemia-diabetes rat

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU BB BG BR BY CA CN CZ FI HU JP KR KZ LK LV MG MN MW NO NZ PL RO RU SD SI SK TT UA US UZ

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA