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WO1993019774A1 - Composition contenant de l'amyline et eventuellement de l'insuline pour le traitement de l'anorexie et de maladies apparentees - Google Patents

Composition contenant de l'amyline et eventuellement de l'insuline pour le traitement de l'anorexie et de maladies apparentees Download PDF

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Publication number
WO1993019774A1
WO1993019774A1 PCT/US1993/003426 US9303426W WO9319774A1 WO 1993019774 A1 WO1993019774 A1 WO 1993019774A1 US 9303426 W US9303426 W US 9303426W WO 9319774 A1 WO9319774 A1 WO 9319774A1
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WO
WIPO (PCT)
Prior art keywords
amylin
patient
insulin
increase
anorexia
Prior art date
Application number
PCT/US1993/003426
Other languages
English (en)
Inventor
Timothy J. Rink
Andrew A. Young
Original Assignee
Amylin Pharmaceuticals, 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 Amylin Pharmaceuticals, Inc. filed Critical Amylin Pharmaceuticals, Inc.
Publication of WO1993019774A1 publication Critical patent/WO1993019774A1/fr

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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
    • A61K38/22—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
    • A61K38/28—Insulins

Definitions

  • This invention relates to treatment of anorexia and related states.
  • Anorexia defined as the lack or the loss of appetite for food (Dorland's Illustrated Medical Dictionary, 24 edition, .B. Saunders Company, Philadelphia, 1965) has multiple etiologies. It is commonly associated with cachexia, "a profound and marked state of constitutional disorder, general ill health and malnutrition” [idem] . Common examples of conditions associated with anorexia and cachexia are anorexia nervosa, certain infectious dis ⁇ eases, and malignancy.
  • Anorexia nervosa is a serious psychiatric disorder affecting predominantly women (94-96%) in the 13-30 age range. Between 1% (Crisp et al., 128 Br. J. Psychiatry 549, 1976) and 3% (Ballot et al., 59 S.A r. Med. J. 992, 1981) of young women may be affected. The morbitidy and mortality from this condition are considerable. Two years from diagnosis, 4-6% have died and only 50% have achieved a normal weight. There are multiple endocrine and meta-
  • TNF tumor necrosis factor
  • Examples of patients requir ⁇ ing parenteral nutrition or other nutritional support include those with inflammatory bowel diseases, patients with resected bowel, severe preoperative malnutrition and acute pancreatitis (Howard, In: Harrisons Principals of Internal Medicine 12th Edition. Wilson et al. (eds) McGraw-Hill, New York 1991, p. 429) .
  • a patient suffering from anorexia may have fasting plasma amylin and insulin concentrations below the normal range, and in fact near the range measured by Type 1 diabetics.
  • Applicant believes that patients suffering from cachexia or receiv- ing parenteral nutrition (i.e. , nutrition except oral nutrition, e.g. , intravenous) have reduced amylin and/or insulin levels.
  • parenteral nutrition i.e. , nutrition except oral nutrition, e.g. , intravenous
  • the amount of the hor ⁇ mones (amylin and insulin) that are administered should preferably be sufficient to increase the hormone plasma levels of the patient to normal levels observed in the general population.
  • the invention features a method for treatment of a patient suffering from anorexia by administering amylin or an analog thereof to the patient in an amount sufficient to increase the amylin level in the plasma of the patient.
  • the invention features methods for treatment of cachectic patients and those ' undergoing parenteral nutrition by similarly administering amylin in an amount sufficient to increase the amylin plasma level.
  • the invention features co-administering insulin to the patient in an amount sufficient to increase insulin plasma level; and the amylin and insulin are provided in an amount suf ⁇ ficient to increase the level of adipose tissue in the patient.
  • the amount of amylin provided is sufficient to increase liver glycogen stores.
  • Insulin and amylin in the patient will act together to enhance the deposition of body fat.
  • Insulin will enhance the uptake of glucose into fat cells and will enhance the transfer of lipid into fats cells via activation of lipoprotein lipase at adipose tissue capillaries.
  • Amylin will enhance the hepatic supply of lactate, a favored lipogenic substrate (Carmona &• Freedland 119 J.
  • the invention features a method for treating a patient that is deficient in adipose tissue by administering amylin and/or insulin as described above in an amount sufficient to increase the amount of adipose tissue in that patient.
  • amylin and/or insulin as described above in an amount sufficient to increase the amount of adipose tissue in that patient.
  • the method includes the step of identifying a mammal having the above-noted conditions, prior to the administering step.
  • amylin is used in this application as defined by Young et al., U.S. application Serial No. 07/640,478, filed January 10, 1991, entitled “Hypergly- cemic Compositions", which (including drawings) is hereby incorporated by reference.
  • amylin which is synthesized and secreted from the beta cells of the pancreas.
  • Amylin functions along with insulin, which is stored and released from the same pancreatic beta cells, to reg ' ulate fuel metabolism.
  • Amylin acts through receptors located in skeletal muscle to increase glycogen turnover in this tissue, believed to result in an increased return to the bloodstream of lactate, which is a major precursor of hepatic gluconeogenesis.
  • Amylin cosecretion with insulin after meals therefore results in restoration of hepatic glycogen content and limits the potential which would otherwise exist for insulin to induce hypoglycemia.
  • Administration of amylin to anesthetized rats produces large increases in blood lactate levels, presumably through a direct effect upon skeletal muscle glycogen breakdown and glycolysis. Increased blood lactate content is followed rapidly by • increased blood glucose levels, believed to result from provision of gluconeogenic pre ⁇ cursors in the form of lactate to the liver.
  • amylin analogue includes derivatives of amylin or other reagents acting as agonists at an amylin receptor, or having those biological properties described above.
  • analogue is meant to include human amylin equivalents known to those of ordinary skill in the art.
  • various amino acids in the amylin sequence can be substituted with equivalent amino acids in a manner which has little (i.e. , reduces activity less than 20%) or no effect on the biological activity of the amylin, as measured in the assay described above.
  • neutral amino acids can be replaced with other neutral amino acids, and charged amino acids replaced with equiv- alently charged amino acids.
  • one or more amino acids may be deleted from the polypeptide if such deletion has little or no affect on the biological activ ⁇ ity of the human amylin.
  • Such variations in the amino acid sequence of the human amylin are readily designed by those of ordinary skill in the art.
  • identifying is meant to include noting the symp ⁇ toms or characteristics of anorexia or cachectic condi ⁇ tions. Such symptoms are well known in the art. It also includes chemical or biochemical assays which indicate such conditions, or their equivalent.
  • insulin is meant a polypeptide or its equivalent useful in regulation of blood glucose levels.
  • a general description of such insulins is provided in Goodman and Gilman, "The pharmacological basis of therapeutics, 7th ed., Maxmillan Pub. Co. at e.g. , p. 1501, et seq. (1985) .
  • Such insulins can be fast acting, intermediate acting, or long acting. .Id. at 1502.
  • Various derivatives of insulin exist and are useful in this invention. See e.g. , U.S. Patents, 5,049,547, 5,028,587, 5,028,586, 5,016,643. Insulin peptides are also useful (see e.g.. U.S.
  • Patent 5,008,241 as are analogues (see e.g.. U.S. Patent 4,992,417 and 4,992,418).
  • Such insulin can be adminis ⁇ tered by any standard route, including nasal administra ⁇ tion, see e.g. , U.S. Patents 4,988,512 and 4,985,242, and 2 BioWorld Today, No. 125, 1, 1991.
  • Other features and advantages of the invention will be apparent from the following description of the pre ⁇ ferred embodiments thereof, and from the claims.
  • Fat Deficient Conditions such as anorexia nervosa, cachectic con ⁇ ditions and the general condition of patients receiving intravenous nutrition or other related conditions may be treated in this invention. In each of these conditions there is either progressive loss of both adipose tissue and lean body mass or failure to increase these from a base of marked established loss.
  • amylin is a controller of fuel cycling from muscle to liver and liver to peripheral tissues. Without being bound to any particular theory, applicant believes that this is due, at least in some part, to-promotion of Cori cycling of carbohydrate from skeletal muscle glycogen to liver glycogen and by the provision of hepatic substrate for triglyceride synthesis. Applicant believes that activation of these pathways improves the efficient storage of food-derived substrates in liver and in adipose tissue in the above-exemplified conditions. Thus, the combined use of amylin and insulin in which amylin serves to provide hepatic substrate and insulin promotes hepatic production of triglyceride and lipogenesis in adipose tissue is beneficial.
  • adipose tissue Promotion of formation of adipose tissue is critical to normal health not only as a concentrated store of energy for use in fasting or exercise, but subcutaneous fat especially is important in establishing the body contours and cushioning of the underlying tissues. Bed sores, for example, may be caused or exacerbated by loss of adipose tissue.
  • Amylin deficiency in Type 1 diabetics has been pro ⁇ posed as a pathologic basis for difficulties in achieving good glycemic control with insulin therapy.
  • Applicant has discovered that an anorexic patient has fasting plasma amylin and insulin concentrations below the normal range, and in fact near the range measured in Type 1 diabetics.
  • anorexia nervosa is an amylin, and possibly insulin, deficient state which can be treated by administration of amylin and/or insulin.
  • compositions or products according to the invention may conveniently be provided in the form of solutions suitable for parenteral or nasal or oral administration.
  • amylin or insulin in many cases, it will be convenient to provide an amylin or insulin in a single solution for administration together. In other cases, it may be more advantageous to administer amylin and insulin separately, A suitable administration regime may best be determined by a doctor for each patient individually. It will generally be preferable to formulate such that the molar ratio of amylin and insulin for the treatment is between 1:100 and 10:1. Most preferably between 1:20 and 1:5.
  • the products of the invention are amphoteric they may be utilized as free bases, as acid addition salts or as metal salts.
  • the salts must, of course, be pharma- ceutically acceptable, and these will include metal salts, particularly alkali and alkaline earth metal salts, e.g. , potassium or sodium salts.
  • metal salts particularly alkali and alkaline earth metal salts, e.g. , potassium or sodium salts.
  • a wide variety of pharmaceu ⁇ tically acceptable acid addition salts are available. These include those prepared from both organic and inor- ganic acids, preferably mineral acids. Typical acids which may be mentioned by way of example include citric, succinic, lactic, hydrochloric and hydrobromic acids. Such products are readily prepared by procedures well known to those skilled in the art.
  • the products of the invention will normally be pro ⁇ vided as parenteral compositions for injection or infu ⁇ sion. They can, for example, be suspended in an inert oil, suitably a vegetable oil such as sesame, peanut, or olive oil. Alternatively, they can be suspended in an aqueous isotonic buffer solution at a pH of about 5.6 to 7.4.
  • useful buffers include sodium citrate-citric acid and sodium phosphate-phosphoric acid.
  • the desired isotonicity may be accomplished using sodium chloride or other pharmaceutically acceptable agents such as dextrose, boric acid, sodium tartrate, propylene glycol or other inorganic or organic solutes.
  • Sodium chloride is preferred particularly for buffers containing sodium ions.
  • solutions of the above compositions may be thickened with a thickening agent such as methyl cel ⁇ lulose. They may be prepared in emulsified form, either water in oil or oil in water. Any of a wide variety of pharmaceutically acceptable emulsifying agents may be employed including, for example acacia powder, or an alkali polyether alcohol sulfate or sulfonate such as a Triton.
  • a thickening agent such as methyl cel ⁇ lulose.
  • emulsifying agents including, for example acacia powder, or an alkali polyether alcohol sulfate or sulfonate such as a Triton.
  • the therapeutically useful compositions of the inven ⁇ tion are prepared by mixing the ingredients following gen ⁇ erally accepted procedures.
  • the selected components may be simply mixed in a blender or other standard device to produce a concentrated mixture which may then be adjusted to the final concentration and viscosity by the addition of water or thickening agent and possibly a buffer to control pH or an additional solute to control tonicity.
  • compositions will be provided in dosage unit form containing an amount of amylin and/or insulin which will be effective in one or multiple doses to control adipose tissue formation at the selected level.
  • an effective amount of therapeutic agent will vary with many factors including the age and weight of the patient, the patient's physical condition, the blood sugar level to be obtained, and other factors.
  • Typical dosage units for treatment of anorexia and related conditions will contain from about 0.1 to 10 mg of an amylin and about 0.1 to about 1.0 mg of an insulin.
  • compositions useful in the inven ⁇ tion are formulated by standard procedure. These compo ⁇ sitions are also administered by standard procedure. Suitable doses are readily determined by those in the art, examples of which are provided above.

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

Abstract

Procédé de traitement d'un malade souffrant d'anorexie ou d'une maladie apparentée au moyen de l'administration d'amyline ou d'un de ses analogues et/ou d'insuline en quantité suffisante pour augmenter les niveaux d'amyline et/ou d'insuline dans le plasma du patient.
PCT/US1993/003426 1992-04-03 1993-04-05 Composition contenant de l'amyline et eventuellement de l'insuline pour le traitement de l'anorexie et de maladies apparentees WO1993019774A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US86250092A 1992-04-03 1992-04-03
US07/862,500 1992-04-03

Publications (1)

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WO1993019774A1 true WO1993019774A1 (fr) 1993-10-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021026A2 (fr) * 2003-08-29 2005-03-10 Amylin Pharmaceuticals, Inc. Procedes pour traiter ou ameliorer des maladies et des troubles associes a la ghreline

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289287A2 (fr) * 1987-04-27 1988-11-02 Amylin Pharmaceuticals, Inc. Peptides amyloides
EP0309100A2 (fr) * 1987-08-26 1989-03-29 Amylin Pharmaceuticals, Inc. Emploi de l'amyline ou CGRP pour le traitement du diabète sucré
EP0408284A2 (fr) * 1989-07-08 1991-01-16 Amylin Pharmaceuticals, Inc. Amyline pour le traitement des troubles osseuses
EP0408294A2 (fr) * 1989-07-10 1991-01-16 Amylin Pharmaceuticals, Inc. Utilisation d'un antagonist de amyline pour l'obtention d'un médicament destiné au traitement de l'obésitÀ© et de l'hypertonie, et des troubles connexes

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289287A2 (fr) * 1987-04-27 1988-11-02 Amylin Pharmaceuticals, Inc. Peptides amyloides
EP0309100A2 (fr) * 1987-08-26 1989-03-29 Amylin Pharmaceuticals, Inc. Emploi de l'amyline ou CGRP pour le traitement du diabète sucré
EP0408284A2 (fr) * 1989-07-08 1991-01-16 Amylin Pharmaceuticals, Inc. Amyline pour le traitement des troubles osseuses
EP0408294A2 (fr) * 1989-07-10 1991-01-16 Amylin Pharmaceuticals, Inc. Utilisation d'un antagonist de amyline pour l'obtention d'un médicament destiné au traitement de l'obésitÀ© et de l'hypertonie, et des troubles connexes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BIOCHEM. BIOPHYS. RES. COMMUN., VOL. 180, NO. 3, PAGE(S) 1513-17 14 November 1991, IWAMOTO, YASUHIKO ET AL. 'Additive effect of islet amyloid polypeptide (IAPP/amylin) and insulin on 2-deoxyglucose uptake in mouse pancreatic acini' *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005021026A2 (fr) * 2003-08-29 2005-03-10 Amylin Pharmaceuticals, Inc. Procedes pour traiter ou ameliorer des maladies et des troubles associes a la ghreline
WO2005021026A3 (fr) * 2003-08-29 2005-04-14 Amylin Pharmaceuticals Inc Procedes pour traiter ou ameliorer des maladies et des troubles associes a la ghreline

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