WO1993019774A1

WO1993019774A1 - Amylin and possibly insulin containing composition for the treatment of anorexia and related states

Info

Publication number: WO1993019774A1
Application number: PCT/US1993/003426
Authority: WO
Inventors: Timothy J. Rink; Andrew A. Young
Original assignee: Amylin Pharmaceuticals, Inc.
Priority date: 1992-04-03
Filing date: 1993-04-05
Publication date: 1993-10-14

Abstract

Method for treatment of a patient suffering from anorexia or a related condition by administering amylin or an analog thereof and/or insulin to the patient in an amount sufficient to increase amylin and/or insulin levels in the plasma of the patient.

Description

DESCRIPTION

AMYLIN AND POSSIBLY INSULIN CONTAINING COMPOSITION FOR THE TREATMENT OF ANOR XIA AND RELATED STATES

Background of the Invention

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-

. bolic abnormalities present, most of which are believed to be secondary to the malnutrition. A serious complication of the condition is osteoporosis, which can involve both * the spine and peripheral bones. At present there is no specific treatment for anorexia nervosa, although multiple approaches have been tried (Piazza, Piazza & Rollins Cotmor. Psychiatry 21:177-189 1980) .

In experimental animals, infection with various agents such as Mycobacterium bovis (Carswell: e_t al. Proc. Natl. Acad. Sci. U.S.A. 73:3666-3670 1975) caused the appearance of a blood factor that caused necrosis of tumors in mice (tumor necrosis factor, TNF) . In a differ¬ ent line of investigation, an agent produced in response

SUBSTITUTE SHEET to infection with Trypanosoma brucei produced unexpected weight loss an wasting (Rouzer & Cerami Mol. Biochem. Parasitol 2:31-38 1980) , and was termed cachexin. TNF and cachexin have since been shown to be the same 17kD pro- tein, produced by activated macrophages. It stimulates several aspects of the immune response. Injected into animals, it produces many of the features of cachexia, including anorexia, bone resorption, and the inhibition of fat uptake into adipocytes. It has been proposed that this agent, which might be produced by tumor cells, or as a host response, could account for some of the cachexia of cancer (Cerami et al. Recent Procr. Horm. Res. 43:99-112 1987) . However, the association of cachexin/TNF with malignancy is the subject of conflicting reports. Nutritional support via either enteral (via the gut) or parenteral (e.cr. , intravenous) therapy is indicated in patients unable to take sufficient nutrition by mouth, and who are therefore at risk for the complication of malnu¬ trition. Therapy attempts to maintain anabolism (buildup of body substance stores) and avert catabolism (break¬ down) . To this end, insulin is commonly added to intra¬ venously infused nutrients. 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) .

Summary of the Invention Applicant has discovered that 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. Thus, applicant proposes that patients suffering from anorexia and cachectic states, as well as patients undergoing parenteral nutrition, be administered amylin with or without insulin. Such administration will preferably increase adipose tissue in such patients and thus be of significant benefit. 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. For example, in a patient having a level of insulin similar to that in a Type 1 diabetic, it is necessary to administer about 1 mg per day of amylin and insulin together in a ratio of amylin to insulin between 1:100 and 10:1. Thus, in a first aspect 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. In related aspects, 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.

In preferred embodiments of the above aspects, 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. For example, 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. Nutr. 1304, 1989) . In another related aspect, 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. Those in the art will recognize that standard procedures can be used to measure the increase in such adipose tissues, and to identify those patients which are deficient in adipose tissue levels. In preferred embodiments, the method includes the step of identifying a mammal having the above-noted conditions, prior to the administering step.

The term "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. For example, it includes the peptide hormone referred to as 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. These phy¬ siological and pharmacological effects.of amylin form the basis for its therapeutic indications in treatment of Type 1 diabetes and hypoglycemia.

The term "amylin analogue" includes derivatives of amylin or other reagents acting as agonists at an amylin receptor, or having those biological properties described above.

The term "analogue" is meant to include human amylin equivalents known to those of ordinary skill in the art. For example, 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. For example, neutral amino acids can be replaced with other neutral amino acids, and charged amino acids replaced with equiv- alently charged amino acids. In addition, 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.

By "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.

By "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.

Description of the Preferred Embodiments Fat Deficient Conditions 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.

Applicant has found that 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.

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. When such a patient was administered a standard 75 g glucose oral load there was a very small transient devia¬ tion of amylin and insulin levels, markedly lower than that seen in normal subjects. Thus, it appears that anorexia nervosa is an amylin, and possibly insulin, deficient state which can be treated by administration of amylin and/or insulin.

While this proposal is counter to reports that amylin can suppress appetite (which is clearly an undesirable feature for treatment of anorexia or cachectic states) , applicant believes that the appetite suppressant effects of amylin is seen only at very high doses and may be short lived. Indeed, applicant has discovered tha ^"in toxico¬ logical studies with amylin in both rats and dogs, where two weeks of amylin administration were used, there was no reduction in food intake or weight in the animal. As with anorexia, applicant believes that both cachectic states and patients receiving total parenteral nutrition are amylin and/or insulin deficient states and thus, appropriate for amylin replacement or augmentation therapy.

Compositions

Compositions or products according to the invention may conveniently be provided in the form of solutions suitable for parenteral or nasal or oral administration.

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.

Since 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. 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.

If desired, 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. The therapeutically useful compositions of the inven¬ tion are prepared by mixing the ingredients following gen¬ erally accepted procedures. For example, 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.

For use by the physician, the 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. As will be recognized by those in the field, 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.

Methods

As defined above, 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.

Other embodiments are within the following claims.

Claims

1. A method for treatment of a patient suffering from anorexia comprising the step of: administering amylin or an analog thereof to said patient in an amount sufficient to increase the amylin level in the plasma of said patient.

2. A method for treatment of a cachectic patient or a patient undergoing parenteral nutrition comprising the step of: administering amylin or an analogue thereof to said patient in an amount sufficient to increase the amylin level in the plasma of said patient.

3. The method of claim 1 or 2 further comprising administering insulin to said patient in an amount suffi- cient to increase the insulin level in said plasma.

4. The method of claim 3 wherein said amylin or insulin are provided in an amount sufficient to increase level of adipose tissue in said patient.

5. The method of claim 1 or 2 wherein said amylin is provided in an amount sufficient to increase level of adipose tissue in said patient.

6. The method of claim 1 wherein said amount of amylin administered is sufficient to increase the anabolic effect of plasma amylin within the liver, and thereby increase glycogen levels by glycogenesis.

7. The method of claim 1 wherein said insulin and amylin are provided in an amount sufficient to enhance mobilization of lactate from muscle to form fat in the liver.

8. A method for treating a patient that is defi¬ cient in adipose tissue by administering amylin and/or insulin in an amount and ratio sufficient to increase adipose tissue in said patient.