WO1994021279A1 - Nutrient formulations and methods of treating malnutrition in aids - Google Patents

Nutrient formulations and methods of treating malnutrition in aids Download PDF

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Publication number
WO1994021279A1
WO1994021279A1 PCT/US1994/003013 US9403013W WO9421279A1 WO 1994021279 A1 WO1994021279 A1 WO 1994021279A1 US 9403013 W US9403013 W US 9403013W WO 9421279 A1 WO9421279 A1 WO 9421279A1
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growth hormone
human growth
formulation
amount
person
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PCT/US1994/003013
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French (fr)
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Michael M. Rothkopf
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Rothkopf Michael M
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Priority to AU64498/94A priority Critical patent/AU6449894A/en
Publication of WO1994021279A1 publication Critical patent/WO1994021279A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • 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
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2

Definitions

  • This invention relates to nutrient formulations and methods of treatment of malnutrition in persons having AIDS and ALDS-related diseases.
  • AIDS is an abbreviation for acquired immunodeficiency syndrome, a disease characterized by opportunistic infections (e.g., Pneumocystis carini pneumonia, candidiasis, isosporiasis, cryptococcosis, toxoplasmosis) and malignancies (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma) in immunocompromised persons.
  • AIDS is caused by the human immunodeficiency virus ("HIV") which is currently believed to be transmitted by intimate sexual contact or blood.
  • the HTV virus selectively attacks T4 lymphocytes, a subpopulation of lymphocytes of the immune system, resulting in reduction in the number of T4 lymphocytes and a change in their function along with the eventual collapse of the immune system.
  • IGF-1 somatomedin
  • somatomedin somatomedin
  • administration of growth hormone raises the resting energy expenditure (REE) of a person at least 20 to 25% and can increase the metabolic imbalance which causes the breakdown of body muscle and body stores of protein and energy (glycogen and fat).
  • FIG. 1 is a bar graph showing the mean change in IGF-1 plasma levels in a group of five patients from adniinistration of growth hormone.
  • Period 1 shows the baseline IGF-1 level when TPN is administered for thirty days.
  • Period 2 shows the IGF-1 level after the adierinistrarion of growth hormone for thirty days.
  • FIG. 2 is a bar graph showing the mean change in the same a group of five patients in nitrogen balance from administration of growth hormone.
  • Period 1 shows the nitrogen balance when total parenteral nutrition (TPN) is administered for thirty days.
  • Period 2 shows the nitrogen balance when growth hormone is administered with TPN for the next thirty days.
  • Period 3 shows the nitrogen balance when TPN alone is administered for the next thirty days.
  • FIG. 3 is a bar graph showing the mean change in the same a group of five patients in fat oxidation and in fat balance levels.
  • Period 1 shows the fat oxidation and fat balance levels when (TPN) is administered for thirty days.
  • Period 2 shows the fat
  • Period 3 shows the fat oxidation and fat balance levels when TPN alone is administered for the next thirty days.
  • FIG. 4 is a bar graph showing the mean changes in carbohydrate oxidation and carbohydrate balance levels.
  • Period 1 shows the carbohydrate oxidation and carbohydrate balance levels when (TPN) is admimstered for thirty days.
  • Period 2 shows the carbohydrate oxidation and carbohydrate balance levels when growth hormone is administer with TPN for the next thirty days.
  • Period 3 shows the carbohydrate oxidation and carbohydrate balance levels when TPN alone is admimstered for the next thirty days.
  • FIG. 5 is a bar graph showing the mean changes in protein oxidation and protein balance levels.
  • Period 1 shows the protein oxidation and protein balance levels when (TPN) is administered for thirty days.
  • Period 2 shows the protein oxidation and protein balance levels when growth hormone is administered with TPN for the next thirty days.
  • Period 3 shows the protein oxidation and protein balance levels when TPN alone is adrrii concludedred for the next thirty days.
  • the present invention provides nutrient formulations for persons with AIDS or AIDS-related diseases and for use in treating malnutrition in persons with AIDS or AIDS-related diseases which comprise in combination a metabolically active peptide exhibiting the metabolic effects associated with human growth hormone in an amount sufficient to increase circulating IGF-1 levels more than 40% above the person's baseline plasma IGF-1 level, and a nutritional supplement providing a daily caloric intake of between 100 and 200% of the person's resting energy expenditure. It has surprisingly been found that these nutrient formulations increase nitrogen balance, enhance fat oxidation, and reduce carbohydrate oxidation in the persons being treated.
  • the present invention also provides methods of treating malnutrition in persons with AIDS or ALOS-related diseases by concurrently administering a metabolically active peptide exhibiting the metabolic effects associated with human growth
  • An advantage of these nutrient formulations and methods is that nutritional repletion of the persons being treated is stimulated without increasing their metabolic demand or respiratory quotient, which increases occur when conventional hypercaloric nutritional supplementation with high carbohydrate loading is administered.
  • nutrient formulations and methods of treating persons having malnutrition associated with AIDS or AIDS-related diseases are provided.
  • the nutrient formulations combine nutritional supplementation with the
  • diseases is obtained by administering nutrient formulations providing in combination a metabolically active peptide in an amount sufficient to increase the circulating IGF-1 level to more than 40% above baseline IGF-1 level before treatment, and a nutritional supplement in an amount providing a daily caloric intake in the range of from about 100 to 200% of the person's baseline resting energy expenditure (REE), preferably from about 130 to 170% of the patient's baseline REE.
  • nutrient formulations providing in combination a metabolically active peptide in an amount sufficient to increase the circulating IGF-1 level to more than 40% above baseline IGF-1 level before treatment, and a nutritional supplement in an amount providing a daily caloric intake in the range of from about 100 to 200% of the person's baseline resting energy expenditure (REE), preferably from about 130 to 170% of the patient's baseline REE.
  • REE resting energy expenditure
  • the "treatment of malnutrition associated with AIDS or AIDS-related diseases” includes administration of the formulations described below to prevent the nutritional depletion known to occur in these diseases, as well as the treatment of malnutrition resulting from such diseases.
  • the term "metabolically active peptide” refers to those peptides which exhibit the metabolic effects associated with human pituitary growth hormone (hGH) and increase IGF-1 levels in vivo by more than 40% above the baseline IGF-1 level before treatment.
  • hGH human pituitary growth hormone
  • a normal baseline IGF-1 level is approximately 140 ng/ml.
  • the baseline IGF-1 level is increased in vivo by more than 120% above the baseline IGF-1 level before treatment, and more preferably between about 135 to 400% above the baseline IGF-1 level before treatment.
  • Metabolically active peptides having such effect comprise peptides or peptide analogs known to bind to human growth hormone releasing factor receptors; human growth hormone receptors or IGF-1 receptors; human growth hormone; human growth hormone analogs; synthetic or naturally occurring peptides having primary structural homology to the amino acid residues of a particular region of human growth hormone; human growth hormone releasing factor (hGRF); human growth hormone releasing factor analogs; and the somatomedins per. se, including somatomedin analogs and somatomedin C/IGF-1.
  • Human growth hormone stimulates the production of somatomedins, including IGF-1, in the liver which are released into the blood and produce many of the anabolic effects of human growth hormone. Merck Index. 11th ed., paragraphs 8670, 8672 (1989); Harper, H.A., et al., Review of Physiological Chemistry. 16th ed., pp. 472, 502 (1977). For example, much of the insulin-like activity in the blood is due to the somatomedins released from the liver as a result of human growth hormone. Id,.
  • the metabolic effects attributable to human growth hormone, human growth hormone releasing factor, somatomedins and their respective analogs, result from the increase of the plasma level of IGF-1.
  • Human growth hormone is a peptide whose isolation and structure is
  • hGH is a relatively high molecular weight polypeptide consisting of 188-191 amino acid residues and having a secondary structure provided by two disulfide bridges linking cysteine residues at particular positions in the molecule (see Li Patent No. 3,853,832 at column 1, lines 21-30, and the somewhat different characterization in Jones U.S. Patent No. 4,699,897, at column 2, lines 59-66.)
  • hGH is a potent anabolic hormone normally produced by the anterior pituitary gland, which produces a variety of metabolic effects. It affects the metabolic processes of the body by increasing the rate of cellular protein synthesis as well as the utilization of amino acids, and decreasing protein degradation along with the rate of use of carbohydrates for the production of energy in the body. Thus, hGH is known to increase nitrogen and protein balance, increase fat oxidation and decrease carbohydrate
  • Human growth hormone analogs useful as metabolically active peptides in accordance with this invention include methionyl-hGH.
  • Metabolically active peptides which have primary structural homology to a particular region within hGH comprise those biologically active synthetic peptides disclosed in Jones et al. U.S. Patent 4,699,897, granted October 13, 1987, the disclosure of which is incorporated by reference herein. Specifically, such peptides comprise those having primary structural homology to a continuous sequence of the amino acid residues of hGH in a region spanning positions 32 to 46, i.e., "hGH 3M6 ", NH 2 -Glu-Glu-Ala-Tyr- ne-Pro-Lys-Glu-Gln-Lys-Tyr-Ser-Phe-Leu-Gln-COOH.
  • peptides are known to exist or can be synthesized which bind to the same receptor as human growth hormone and would thus have the same effect as human growth hormone.
  • a growth hormone-like substance produced by the plerocercoid stage of the tapeworm Spirometra mansonoides is known to mimic the effects of human growth hormone. (See, Phares, C.K., "Use of receptor affinity chromatography in purification of the growth hormone like factor produced by pleroceroids of the tape worm Spirometra mansonoides", J. Recept Res. 8:645-665 (1988)).
  • hGRF Human growth hormone-releasing factor
  • hGH growth hormone
  • metabolically active peptides hereof comprise those analogs more fully described in the
  • Other peptides are known or can be synthesized which bind to the same receptor as human growth hormone releasing factor and would have the same effect.
  • the somatomedins which may comprise the metabolically active peptides utilized in accordance with this invention are known in the literature, having been described in "Somatomedins" The Merck Index. 10 Ed., pg. 1246, the disclosure of which is incorporated by reference herein.
  • the somatomedins are peptides having molecular weights of between 4500 and 7800 Daltons, which circulate in the body bound to larger carrier proteins. The somatomedins appear in the circulation within hours after hGH administration and have a half-life of about 12 hours.
  • IGF-1 also known as Somatomedin-C, is one of the somatomedins known to cause the same metabolic effects as hGH.
  • IGF-1 is a basic 70 amino acid, single chain polypeptide with three disulfide bonds and a molecular weight of about 7700 Daltons.
  • IGF-1 exerts its effect by binding to specific receptors.
  • IGF-1 analogs which bind to these receptors, may be synthesized and can be used in place of IGF-1. If
  • IGF-1 levels are deterrnined by obtaining samples of blood by venipuncture into tubes containing EDTA. Plasma is separated by centrifugation, placed into polypropylene tubes and rapidly cooled to 0°C. IGF-1 levels in the plasma are then measured by radioimmunoassay techniques.
  • IGF-1 plasma level of IGF-1 above about 40% of the baseline IGF-1 level or about 196 ng/ml
  • plasma preferably above about 120% or about 308 ng/ml plasma; and more preferably between about 135% to 400% or about 330 and 670 ng/ml plasma. Since plasma levels of IGF-1 may vary with age, sex, nutritional status and other factors, it is preferable that a baseline level of IGF-1 be established before the administration of metabolically active peptides. It is currently understood that AIDS results in a lower IGF-1 level and an attenuated IGF-1 response.
  • the baseline level of IGF-1 refers to the person's untreated IGF-1 plasma level.
  • the resulting increase in IGF-1 levels above the baseline IGF-1 level attributable to the metabolically active peptides is more than 40% or 56 ng/ml, preferably between about 200 and 400% or 140 and 420 ng/ml, more preferably between about 240 to 335% or 196 to 330 ng/ml.
  • metabolically active peptides within the foregoing class which, as illustrated hereinafter, increase the nitrogen and protein balance, increase fat oxidation and decrease carbohydrate oxidation in persons having AIDS or AIDS-related diseases, whether by reason of the increase of IGF-1 levels or otherwise.
  • the metabolically active peptide preferably hGH, may be administered by any desired route, e.g., intranasally, sublingually, rectally, intramuscularly, intravenously
  • metabolically active peptide can be administered
  • an implant suitable for use in the present invention can take the form of a pellet which slowly dissolves after being implanted or a biocompatible delivery module well known to those skilled in the art.
  • Such well known dosage forms and modules are designed such that the active ingredients are slowly released over a period of several days to several weeks.
  • the metabolically active peptide comprises recombinant hGH
  • the specific dosage may vary depending upon the amount necessary to import the requisite metabolic activity in vivo.
  • the metabolically active peptide is concurrently administered, in accordance with this invention, with a nutritional supplement, the latter providing a daily caloric content in the range of from about 100 to 200%, preferably from about 130 to 170% of the person's baseline resting energy expenditure (REE), and providing less than about 500 gm of carbohydrate per day.
  • Baseline REE levels are the REE levels established before the administration of any nutritional supplementation.
  • the REE is a recognized parameter which may be predicted by application of the Harris-Benedict formula based upon the height, weight, age and sex of the person. Harris, et al, "A Biometric Study of the Basal Metabolism in Man", Carnegie Inst. Washington Pub. 279, Washington, D.C. (1919). The REE may be calculated for an individual person from his oxygen consumption (VO ⁇ , carbon dioxide production (VCO ⁇ and nitrogen excretion by standard indirect calorimetry procedures. Elwyn, D.H. et al., American Journal of Clinical Nutrition, 32:1597-1611 (1979); Swift, et al, "Energy Metabolism and Nutrition", Scarecrow Press, Washington, D.C. (1954); and Consolazio, et al, "Physiological Measurements of Metabolic Function in Man", pages 313-339, McGraw Hill, New York, (1963).
  • Nutritional supplements useful in the treatment hereof comprise, by:
  • the supplement has a carbohydrate content in the range of 200 to 700 grams per day, preferably at least 300 grams per day and preferably less than about 500 grams per day.
  • any commercially available protein source suitable for parenteral nutrition may be utilized in the nutritional supplement.
  • Such protein source may comprise mixtures of essential and non-essential amino acids.
  • a formulation containing essential amino acids comprising isoleucine, leucine, lysine (acetate), methionine, phenylalanine, threonine, tryptophan and valine, and non-essential amino acids comprising alanine, argierine, aspartic acid, glutamic acid, histidine, proline, serine, N-acetyl-L-tyrosine and glycine (commercially available as "Aminosyn II" from Abbott Laboratories) may be utilized in the nutritional supplement.
  • the carbohydrate source incorporated in the nutritional supplement may be
  • the carbohydrate comprises dextrose
  • glycerol incorporated in the fat emulsion utilized as a lipid source.
  • the fat source incorporated in the nutritional supplement may comprise triglycerides, lipids and/or free fatty acids.
  • the fat source may be a conventional fat emulsion incorporating an emulsifier such as a non-ionic surface active agent, egg yolk phospholipids and soybean phospholipids.
  • soybean oil is utilized as the fatty acid source.
  • Electrolytes and trace elements are readily available from various commercial sources.
  • ELDUR FEOSOL containing iron from Smithkline Consumer Division, Philadelphia, PA.
  • Vitamins in many forms are also suitable for use in the present invention. Examples include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pantothenic acid, niacin, pyridoxine, cyanocobalamin, ascorbic acid, biotin, folate and carnitine. These vitamins may be obtained from various commercial sources. For example, M.V.C.
  • Additional examples include AQUA-MEPHYTOL INJEC ⁇ ON from Merck, Sharp and Dohme, West Point, PA, containing vitamin K, and MEGA L-CARNITLNE from Twin Labs, Ronkonkama, NY, containing carnitine.
  • the nutritional supplement may be administered either enterally or parenterally, and may provide the patient's entire nutritional requirements.
  • admmistering enteral nutritional formulations are well known in the art and include oral, nasogastric tube or gastrostomy tube feeding techniques. Methods of providing parenteral nutritional supplementation are also well known in the art and include the use of peripheral catheters or central venous catheters.
  • Enteral supplementation can be provided by administration of the formulation made of the following components:
  • the nutritional supplement is administered by intravenous infusion. It has been shown that the infusion of intravenous lipids alters the patient's body fuel metabolism, thereby permitting caloric expenditure without the risk of a large increase in carbon dioxide production. This facilitates the use of parenteral nutrition in persons with AIDS because it permits them to receive large caloric quantities within tolerable limits of CO 2 production.
  • nutritional supplement either by the same route of administration, or by different routes, provides a pharmaceutical formulation having unique benefits in the treatment of persons suffering from malnutrition associated with AIDS or AIDS-related diseases.
  • benefits include producing a positive nitrogen balance, reduced utilization of carbohydrates, increased fat oxidation and accelerated restoration of lean body mass (LBM) along with decreased respiratory quotient (RQ).
  • LBM lean body mass
  • RQ respiratory quotient
  • TPN total parenteral nutrition
  • REE resting energy expenditure
  • Baseline REE was determined on the date of admission.
  • the TPN formulation consisted of 100 grams of fat (Intralipid 20%, Kabi-Vitrum Labs, Inc.), 200 grams of carbohydrate (dextrose, 20%), 114 grams of protein (Novamine, Kabi-Vitrum Laboratories, Inc.), one ampule of vitamins (M.V.C. 9+3, Lyphomed, Inc.), and one ampule of trace elements (TMA, Abbott Laboratories, Inc.), administered in an amount calculated to 130 times the baseline REE per day.
  • the caloric intake was distributed as follows: 47% fat, 32% carbohydrates and 21% protein; the calorie to nitrogen ratio (Kcal:gm) was about 114:1.
  • TPN plus recombinant biosynthetic human growth hormone (hGH) were simultaneously administered subcutaneously, the hGH being administered at a dose of 30 ug/kg/day.
  • TPN alone was administered to the patients in the same amounts as given in period 1.
  • Total body water was estimated from regression equations relating to age, sex and weight. In order to estimate steady state conditions in each of the thirty day periods studied, the first two days were disregarded. IGF-1 concentration Blood was collected in EDTA ("Lavender") tubes and plasma was
  • Carbohydrate oxidation was 297.9 g/day in period 1 and decreased when hGH was added in period 2 to 217.65 g/day, as shown in FIG 4. Carbohydrate oxidation returned closer to baseline range in period 3 to 250.8 g/day, but not completely, again suggesting a prolonged hGH induced metabolic effect.
  • Free fatty acids Free fatty acids increased from 242.5 microequivalents/1 in period 1 to 244.74 microequivalents/1 in period 2. In period 3, free fatty acid levels declined to 154.9 microequivalents/1.
  • FIGS. 3 to 5 demonstrate the beneficial metabolic changes produced when human growth hormone is administered in addition to TPN.
  • FIG. 3 compares fat oxidation and balance during each of the three periods in the study. During period 1 there is a positive fat balance and positive fat oxidation. However, upon addition of human growth hormone to TPN in period 2 fat oxidation increased and fat balance declined. This effect persisted into period 3. This is beneficial since it indicates that more energy is being derived from the metabolism of fat.
  • FIG. 4 demonstrates that a positive carbohydrate balance is achieved through the addition of human growth hormone to TPN. During period 1, there is a negative carbohydrate balance. However, upon administration of human growth hormone
  • FIG. 5 demonstrates the decreased protein oxidation and increased protein balance achieved though the administration of human growth hormone with TPN. During period 1, there is a positive protein balance. Upon administration of human growth hormone in period 2, protein balance increases even further. A return to pre-hGH

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Abstract

Nutrient formulations and methods of treating persons having malnutrition associated with AIDS or AIDS-related diseases comprising the administration of metabolically active peptides in an amount sufficient to increase circulating IGF-1 levels more than 40 % above the person's baseline IGF-1 plasma level in combination with nutritional supplementation providing a daily caloric intake of between 100 and 200 % of the person's baseline resting energy expenditure.

Description

NUTRIENT FORMULATIONS AND METHODS OF TREATING MAIJ>TCJTRΠTON IN AIDS
Field of the Invention
This invention relates to nutrient formulations and methods of treatment of malnutrition in persons having AIDS and ALDS-related diseases.
Background of the Invention The present invention is directed to nutrient formulations and methods of
treating persons having malnutrition associated with AIDS and AIDS-related diseases. AIDS is an abbreviation for acquired immunodeficiency syndrome, a disease characterized by opportunistic infections (e.g., Pneumocystis carini pneumonia, candidiasis, isosporiasis, cryptococcosis, toxoplasmosis) and malignancies (e.g., Kaposi's sarcoma, non-Hodgkin's lymphoma) in immunocompromised persons. AIDS is caused by the human immunodeficiency virus ("HIV") which is currently believed to be transmitted by intimate sexual contact or blood. The HTV virus selectively attacks T4 lymphocytes, a subpopulation of lymphocytes of the immune system, resulting in reduction in the number of T4 lymphocytes and a change in their function along with the eventual collapse of the immune system.
Malnutrition is a common complication in these persons resulting from the increased energy needed to fight opportunistic infections as well as the reduced oral intake of food. This often results in weight loss which leads to a further decline in the immunocompromised person. Severe weight loss is associated with a poor prognosis and increased mortality. Nutritional repletion regimens have been used in order to stabilize weight loss and eliminate malnutrition in persons having AIDS or AIDS -related diseases.
However, the physiologic response of individuals who suffer from these diseases pose
significant challenges. This is particularly the case since the metabolism of certain nutrients, especially carbohydrates, used in these regimens results in both increased metabolic demands and ventilatory requirements due to excessive quantities of CO2 produced from the metabolism of carbohydrates.
Persons who are chronically ill or malnourished have suppressed somatomedin (IGF-1) levels which generally do not respond to administration of human growth hormone. Furthermore, administration of growth hormone raises the resting energy expenditure (REE) of a person at least 20 to 25% and can increase the metabolic imbalance which causes the breakdown of body muscle and body stores of protein and energy (glycogen and fat).
Malnourished persons with chronic lung disease do not respond to traditional diets because the carbohydrate content increases the amount of carbon dioxide produced which increases their metabolic demands and ventilating requirements. This inventor found that administration of growth hormone to increase circulating somatomedin C levels more than 0.8 U/ml above baseline with a nutritional supplement providing less than 300 grams of carbohydrate per day and a daily caloric intake from 100 to 200% of the patient's baseline resting energy expenditure provided nutritional repletion to these persons (U.S. Patent No. 5,179,080). Such a formulation, however, is contraindicated for persons with AIDS or ALDS-related diseases. Malnourished persons with chronic lung diseases have a normal or low REE, which is typical of most malnourished persons who are generally hypometabolic and have a low REE. Persons with AIDS or AIDS-related diseases who are malnourished are unusual in that they are hypermetabolic, having a high REE which is often 30% above normal. They also are frequently anorexic and refuse an adequate intake of food, although they require a hypercaloric diet due to their hypermetabolic state. The
administration of growth hormone to such hypermetabolic persons would raise their high REE at least an additional 20 to 25% further increasing the metabolic imbalance to the detriment of these malnourished, hypermetabolic persons. Traditional hypercaloric nutritional supplementation formulations must be adjusted for the specialized needs of persons who suffer from AIDS or ALDS-related diseases. Thus, there exists a continuing need for nutritional formulations to treat such diseases and induce the beneficial effects associated therewith.
Brief Description of the Drawings FIG. 1 is a bar graph showing the mean change in IGF-1 plasma levels in a group of five patients from adniinistration of growth hormone. Period 1 shows the baseline IGF-1 level when TPN is administered for thirty days. Period 2 shows the IGF-1 level after the adiriinistrarion of growth hormone for thirty days.
FIG. 2 is a bar graph showing the mean change in the same a group of five patients in nitrogen balance from administration of growth hormone. Period 1 shows the nitrogen balance when total parenteral nutrition (TPN) is administered for thirty days. Period 2 shows the nitrogen balance when growth hormone is administered with TPN for the next thirty days. Period 3 shows the nitrogen balance when TPN alone is administered for the next thirty days. FIG. 3 is a bar graph showing the mean change in the same a group of five patients in fat oxidation and in fat balance levels. Period 1 shows the fat oxidation and fat balance levels when (TPN) is administered for thirty days. Period 2 shows the fat
oxidation and fat balance levels when growth hormone is adπiinister with TPN for the
next thirty days. Period 3 shows the fat oxidation and fat balance levels when TPN alone is administered for the next thirty days.
FIG. 4 is a bar graph showing the mean changes in carbohydrate oxidation and carbohydrate balance levels. Period 1 shows the carbohydrate oxidation and carbohydrate balance levels when (TPN) is admimstered for thirty days. Period 2 shows the carbohydrate oxidation and carbohydrate balance levels when growth hormone is administer with TPN for the next thirty days. Period 3 shows the carbohydrate oxidation and carbohydrate balance levels when TPN alone is admimstered for the next thirty days. FIG. 5 is a bar graph showing the mean changes in protein oxidation and protein balance levels. Period 1 shows the protein oxidation and protein balance levels when (TPN) is administered for thirty days. Period 2 shows the protein oxidation and protein balance levels when growth hormone is administered with TPN for the next thirty days. Period 3 shows the protein oxidation and protein balance levels when TPN alone is adrriinistered for the next thirty days.
Summary of the Invention The present invention provides nutrient formulations for persons with AIDS or AIDS-related diseases and for use in treating malnutrition in persons with AIDS or AIDS-related diseases which comprise in combination a metabolically active peptide exhibiting the metabolic effects associated with human growth hormone in an amount sufficient to increase circulating IGF-1 levels more than 40% above the person's baseline plasma IGF-1 level, and a nutritional supplement providing a daily caloric intake of between 100 and 200% of the person's resting energy expenditure. It has surprisingly been found that these nutrient formulations increase nitrogen balance, enhance fat oxidation, and reduce carbohydrate oxidation in the persons being treated. The present invention also provides methods of treating malnutrition in persons with AIDS or ALOS-related diseases by concurrently administering a metabolically active peptide exhibiting the metabolic effects associated with human growth
hormone in an amount sufficient to increase circulating IGF-1 levels more than 40% above the person's baseline plasma IGF-1 level, and a nutritional supplement providing a daily caloric intake of between 100 and 200% of the person's resting energy expenditure. It has surprisingly been found that these methods increase nitrogen balance, enhance fat oxidation, and reduce carbohydrate oxidation in the persons being treated.
An advantage of these nutrient formulations and methods is that nutritional repletion of the persons being treated is stimulated without increasing their metabolic demand or respiratory quotient, which increases occur when conventional hypercaloric nutritional supplementation with high carbohydrate loading is administered.
Upon further study of the specification and appended claims, further objects and advantages of this invention will become apparent to those skilled in the art.
Detailed Description of the Invention In accordance with the present invention, nutrient formulations and methods of treating persons having malnutrition associated with AIDS or AIDS-related diseases are provided. The nutrient formulations combine nutritional supplementation with the
administration of metabolically active peptides in order to provide nutritional repletion while mim'mizing the increased metabolic demands associated with previously proposed hypercaloric nutritional regimens. In particular, it has been found that substantial improvement in the treatment of malnutrition in persons having AIDS or AIDS-related
diseases is obtained by administering nutrient formulations providing in combination a metabolically active peptide in an amount sufficient to increase the circulating IGF-1 level to more than 40% above baseline IGF-1 level before treatment, and a nutritional supplement in an amount providing a daily caloric intake in the range of from about 100 to 200% of the person's baseline resting energy expenditure (REE), preferably from about 130 to 170% of the patient's baseline REE.
As used herein, the "treatment of malnutrition associated with AIDS or AIDS-related diseases" includes administration of the formulations described below to prevent the nutritional depletion known to occur in these diseases, as well as the treatment of malnutrition resulting from such diseases.
It has been found that the administration of nutrient formulations providing a metabolically active peptide in conjunction with nutritional supplementation significantly increases the nitrogen balance and enhances fat oxidation while reducing carbohydrate oxidation in persons with AIDS or AIDS-related diseases. The combined therapy thus provides a technique for refeeding such persons without increasing metabolic demands and ventilatory requirements associated with the high carbohydrate loading of conventional hypercaloric nutritional supplementation. As used herein, the term "metabolically active peptide" refers to those peptides which exhibit the metabolic effects associated with human pituitary growth hormone (hGH) and increase IGF-1 levels in vivo by more than 40% above the baseline IGF-1 level before treatment. A normal baseline IGF-1 level is approximately 140 ng/ml. Preferably the baseline IGF-1 level is increased in vivo by more than 120% above the baseline IGF-1 level before treatment, and more preferably between about 135 to 400% above the baseline IGF-1 level before treatment. Metabolically active peptides having such effect comprise peptides or peptide analogs known to bind to human growth hormone releasing factor receptors; human growth hormone receptors or IGF-1 receptors; human growth hormone; human growth hormone analogs; synthetic or naturally occurring peptides having primary structural homology to the amino acid residues of a particular region of human growth hormone; human growth hormone releasing factor (hGRF); human growth hormone releasing factor analogs; and the somatomedins per. se, including somatomedin analogs and somatomedin C/IGF-1. Human growth hormone stimulates the production of somatomedins, including IGF-1, in the liver which are released into the blood and produce many of the anabolic effects of human growth hormone. Merck Index. 11th ed., paragraphs 8670, 8672 (1989); Harper, H.A., et al., Review of Physiological Chemistry. 16th ed., pp. 472, 502 (1977). For example, much of the insulin-like activity in the blood is due to the somatomedins released from the liver as a result of human growth hormone. Id,. The metabolic effects attributable to human growth hormone, human growth hormone releasing factor, somatomedins and their respective analogs, result from the increase of the plasma level of IGF-1. Administration of human growth hormone to a patient, by stimulating the production of somatomedins, increases the patient's plasma level of IGF-1. Likewise, administration of human growth hormone releasing factor to a patient stimulates the pituitary to release human growth hormone which, in turn, stimulates the production of somatomedins thereby increasing the patient's plasma level of IGF-1. Merck Index. 11th ed., paragraph 8669 (1989); Harper, H.A., et al. Review of Physiological Chemistry. 16th ed., p. 504 (1977). Adπώiistering somatomedins to a patient will also increase the patient's plasma level of IGF-1.
Human growth hormone (hGH) is a peptide whose isolation and structure is
known (See Li et al., Science. 124, 1293 (1956); Li, et al., Journal of the American
Chemical Society, 88, 2050 (1966); and Atlas of Protein Sequence and Structure, Vol. 5, Supp. 2 pp. 120-121 (1976). It has also been prepared by total syntheses as described, e.g., in Li U.S. Patent No. 3,853,832, granted December 10, 1974 and has also been prepared by recombinant DNA technology. (See "Recombinant Human Growth Hormone" L. M. Fryklund et al., Clinics in Endocrinology and Metabolism 15:3 (August 1986) and Capdevielle, J. et al. "Characterization of Authentic Human GH Produced in E. Coli" Horm. Res. 24:225 (1986)). hGH is a relatively high molecular weight polypeptide consisting of 188-191 amino acid residues and having a secondary structure provided by two disulfide bridges linking cysteine residues at particular positions in the molecule (see Li Patent No. 3,853,832 at column 1, lines 21-30, and the somewhat different characterization in Jones U.S. Patent No. 4,699,897, at column 2, lines 59-66.)
hGH is a potent anabolic hormone normally produced by the anterior pituitary gland, which produces a variety of metabolic effects. It affects the metabolic processes of the body by increasing the rate of cellular protein synthesis as well as the utilization of amino acids, and decreasing protein degradation along with the rate of use of carbohydrates for the production of energy in the body. Thus, hGH is known to increase nitrogen and protein balance, increase fat oxidation and decrease carbohydrate
oxidation. Human growth hormone analogs useful as metabolically active peptides in accordance with this invention include methionyl-hGH.
Metabolically active peptides which have primary structural homology to a particular region within hGH comprise those biologically active synthetic peptides disclosed in Jones et al. U.S. Patent 4,699,897, granted October 13, 1987, the disclosure of which is incorporated by reference herein. Specifically, such peptides comprise those having primary structural homology to a continuous sequence of the amino acid residues of hGH in a region spanning positions 32 to 46, i.e., "hGH3M6", NH2-Glu-Glu-Ala-Tyr- ne-Pro-Lys-Glu-Gln-Lys-Tyr-Ser-Phe-Leu-Gln-COOH. Other peptides are known to exist or can be synthesized which bind to the same receptor as human growth hormone and would thus have the same effect as human growth hormone. For example, a growth hormone-like substance produced by the plerocercoid stage of the tapeworm Spirometra mansonoides is known to mimic the effects of human growth hormone. (See, Phares, C.K., "Use of receptor affinity chromatography in purification of the growth hormone like factor produced by pleroceroids of the tape worm Spirometra mansonoides", J. Recept Res. 8:645-665 (1988)).
Human growth hormone-releasing factor (hGRF) is a 44 amino acid peptide having growth hormone (hGH) releasing activity. As described in Drengler U.S. Patent No. 4,801,456 granted January 31, 1989, hGRF is usually isolated from pancreatic human tumor cells (hpGRF). hpGRF has the structure
H-Tyr-Ala-Asp-Ala-ne-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala- Arg-Ala-Arg-Leu-NH2. Human growth hormone releasing factor analogs within the scope of the
metabolically active peptides hereof comprise those analogs more fully described in the
aforesaid Drengler U.S. Patent No. 4,801,456, at column 1, line 22 - column 2, line 34, the disclosure of which is incorporated by reference herein. Other peptides are known or can be synthesized which bind to the same receptor as human growth hormone releasing factor and would have the same effect.
The somatomedins which may comprise the metabolically active peptides utilized in accordance with this invention are known in the literature, having been described in "Somatomedins" The Merck Index. 10 Ed., pg. 1246, the disclosure of which is incorporated by reference herein. The somatomedins are peptides having molecular weights of between 4500 and 7800 Daltons, which circulate in the body bound to larger carrier proteins. The somatomedins appear in the circulation within hours after hGH administration and have a half-life of about 12 hours. IGF-1, also known as Somatomedin-C, is one of the somatomedins known to cause the same metabolic effects as hGH. IGF-1 is a basic 70 amino acid, single chain polypeptide with three disulfide bonds and a molecular weight of about 7700 Daltons.
IGF-1 exerts its effect by binding to specific receptors. IGF-1 analogs, which bind to these receptors, may be synthesized and can be used in place of IGF-1. If
such analogs were to be used, they would produce the same metabolic effect without increasing the levels of somatomedin levels.
Levels of IGF-1 are measured by radioimmunoassay techniques from commercially available kits utilizing methods disclosed in "Serum Somatoblatin-C
Concentrations in a Rabbit Model of Diabetic Pregnancy" by D'Ercole, et al., Diabetes 33:590-595 (1984). IGF-1 levels are deterrnined by obtaining samples of blood by venipuncture into tubes containing EDTA. Plasma is separated by centrifugation, placed into polypropylene tubes and rapidly cooled to 0°C. IGF-1 levels in the plasma are then measured by radioimmunoassay techniques.
It is currently understood that administration of the foregoing metabolically active peptides results in the synthesis or release in vivo of IGF-1. The metabolic effects attributable to hGH, hGRF or their respective analogs, result from the increase of the
plasma level of IGF-1 above about 40% of the baseline IGF-1 level or about 196 ng/ml
plasma, preferably above about 120% or about 308 ng/ml plasma; and more preferably between about 135% to 400% or about 330 and 670 ng/ml plasma. Since plasma levels of IGF-1 may vary with age, sex, nutritional status and other factors, it is preferable that a baseline level of IGF-1 be established before the administration of metabolically active peptides. It is currently understood that AIDS results in a lower IGF-1 level and an attenuated IGF-1 response.
As used herein, the baseline level of IGF-1 refers to the person's untreated IGF-1 plasma level. The resulting increase in IGF-1 levels above the baseline IGF-1 level attributable to the metabolically active peptides is more than 40% or 56 ng/ml, preferably between about 200 and 400% or 140 and 420 ng/ml, more preferably between about 240 to 335% or 196 to 330 ng/ml. It will, however, be understood that this invention is not restricted to the foregoing mechanism, but comprises the use of metabolically active peptides within the foregoing class which, as illustrated hereinafter, increase the nitrogen and protein balance, increase fat oxidation and decrease carbohydrate oxidation in persons having AIDS or AIDS-related diseases, whether by reason of the increase of IGF-1 levels or otherwise. The metabolically active peptide, preferably hGH, may be administered by any desired route, e.g., intranasally, sublingually, rectally, intramuscularly, intravenously
or subcutaneously. For example, the metabolically active peptide can be administered
parenterally in the form of slow-release subcutaneous implants or targeted delivery systems such as polymer matrices, liposomes, and microspheres. An implant suitable for use in the present invention can take the form of a pellet which slowly dissolves after being implanted or a biocompatible delivery module well known to those skilled in the art. Such well known dosage forms and modules are designed such that the active ingredients are slowly released over a period of several days to several weeks. When the metabolically active peptide comprises recombinant hGH, it is preferred to administer it subcutaneously, at a dosage of at least about 10-150 micrograms per kilogram of body weight per day, preferably between about 30 ug/kg/day to 50 ug/kg/day. Employing other metabolically active peptides, the specific dosage may vary depending upon the amount necessary to import the requisite metabolic activity in vivo.
As indicated hereinabove, the metabolically active peptide is concurrently administered, in accordance with this invention, with a nutritional supplement, the latter providing a daily caloric content in the range of from about 100 to 200%, preferably from about 130 to 170% of the person's baseline resting energy expenditure (REE), and providing less than about 500 gm of carbohydrate per day. Baseline REE levels are the REE levels established before the administration of any nutritional supplementation.
The REE is a recognized parameter which may be predicted by application of the Harris-Benedict formula based upon the height, weight, age and sex of the person. Harris, et al, "A Biometric Study of the Basal Metabolism in Man", Carnegie Inst. Washington Pub. 279, Washington, D.C. (1919). The REE may be calculated for an individual person from his oxygen consumption (VO^, carbon dioxide production (VCO^ and nitrogen excretion by standard indirect calorimetry procedures. Elwyn, D.H. et al., American Journal of Clinical Nutrition, 32:1597-1611 (1979); Swift, et al, "Energy Metabolism and Nutrition", Scarecrow Press, Washington, D.C. (1954); and Consolazio, et al, "Physiological Measurements of Metabolic Function in Man", pages 313-339, McGraw Hill, New York, (1963).
Nutritional supplements useful in the treatment hereof comprise, by
percentage of caloric intake, about 30 to 70% fat, 10 to 60% carbohydrate and 10 to 30% protein, preferably about 40 to 60% fat, 30 to 50% carbohydrates and 15 to 25% protein. They may also incorporate vitamins, electrolytes and mineral micronutrients. As it is preferable to mimmize the increased metabolic demands produced by the administration of carbohydrate, the supplement has a carbohydrate content in the range of 200 to 700 grams per day, preferably at least 300 grams per day and preferably less than about 500 grams per day.
Any commercially available protein source suitable for parenteral nutrition may be utilized in the nutritional supplement. Such protein source may comprise mixtures of essential and non-essential amino acids. For example, a formulation containing essential amino acids comprising isoleucine, leucine, lysine (acetate), methionine, phenylalanine, threonine, tryptophan and valine, and non-essential amino acids comprising alanine, argiriine, aspartic acid, glutamic acid, histidine, proline, serine, N-acetyl-L-tyrosine and glycine (commercially available as "Aminosyn II" from Abbott Laboratories) may be utilized in the nutritional supplement. The carbohydrate source incorporated in the nutritional supplement may be
dextrose, glucose polymers, or starches. Preferably, the carbohydrate comprises dextrose
administered in an amount of less than 500 grams per day. A small proportion, from
about 2 to 5 grams per day may be glycerol, incorporated in the fat emulsion utilized as a lipid source.
The fat source incorporated in the nutritional supplement may comprise triglycerides, lipids and/or free fatty acids. Preferably, the fat source may be a conventional fat emulsion incorporating an emulsifier such as a non-ionic surface active agent, egg yolk phospholipids and soybean phospholipids. Preferably, soybean oil is utilized as the fatty acid source.
Electrolytes and trace elements are readily available from various commercial sources. For example, TRACELYTE π WITH DOUBLE ELECTROLYTES containing sodium, potassium, calcium, magnesium, chloride, gluconate, acetate, zinc (as sulfate), copper (as sulfate), chromium (as chloride) and manganese (as sulfate), Potassium Phosphate Injection, U.S.P. and Magnesium Sulfate Injection, 50%, U.S.P., all from LyphoMed, Inc., Rosemont, IL, may be used. An additional example is ELDUR FEOSOL containing iron from Smithkline Consumer Division, Philadelphia, PA.
Vitamins in many forms are also suitable for use in the present invention. Examples include vitamin A, vitamin D, vitamin E, vitamin K, thiamine, riboflavin, pantothenic acid, niacin, pyridoxine, cyanocobalamin, ascorbic acid, biotin, folate and carnitine. These vitamins may be obtained from various commercial sources. For example, M.V.C. 9 + 3 from LyphoMed, Inc., Melrose Park, IL containing ascorbic acid, vitamin A as retinol, vitamin D as ergocalciferol, tWamine as the hydrochloride, riboflavin as the 5 '-phosphate, pyridoxine as the hydrochloride, niacin as niacinamide, pantothenic acid as dexpanthenol, vitamin E as dl-alpha tocopheryl acetate, biotin, folate as folic acid and cyanocobalamin may be used. Additional examples include AQUA-MEPHYTOL INJECΗON from Merck, Sharp and Dohme, West Point, PA, containing vitamin K, and MEGA L-CARNITLNE from Twin Labs, Ronkonkama, NY, containing carnitine.
The nutritional supplement may be administered either enterally or parenterally, and may provide the patient's entire nutritional requirements. Methods of
admmistering enteral nutritional formulations are well known in the art and include oral, nasogastric tube or gastrostomy tube feeding techniques. Methods of providing parenteral nutritional supplementation are also well known in the art and include the use of peripheral catheters or central venous catheters.
Enteral supplementation can be provided by administration of the formulation made of the following components:
Component Ouantitv
Fish Oil Concentrate 15-85 g
Wheat Germ Oil 20-60 g
Carbohydrates 200-400 g
Proteins 102-124 g
Electrolytes 8700-11500 mg
Trace Elements 13-25 mg
Vitamins 918-2470 mg
Emulsifiers 5-50 g
Stabilizers 0.2-3 g
Distilled Water 1250-1295 ml
Preferably, however, the nutritional supplement is administered by intravenous infusion. It has been shown that the infusion of intravenous lipids alters the patient's body fuel metabolism, thereby permitting caloric expenditure without the risk of a large increase in carbon dioxide production. This facilitates the use of parenteral nutrition in persons with AIDS because it permits them to receive large caloric quantities within tolerable limits of CO2 production.
The co-administration of the aforesaid metabolically active peptide and
nutritional supplement, either by the same route of administration, or by different routes, provides a pharmaceutical formulation having unique benefits in the treatment of persons suffering from malnutrition associated with AIDS or AIDS-related diseases. In particular, such benefits include producing a positive nitrogen balance, reduced utilization of carbohydrates, increased fat oxidation and accelerated restoration of lean body mass (LBM) along with decreased respiratory quotient (RQ). The following example illustrates a preferred treatment of malnutrition associated with AIDS or ALϋS-related diseases. It will be understood that the example is illustrative only, and does not limit the scope of this invention.
Example Five adult male patients with moderate to severe AIDS and malnutrition were studied. Venous access was established using either a peripheral catheter (Aniocath, Deseret, Inc.) or a Hickman central venous catheter (Davol, Inc.)
On the first thirty days following the commencement of treatment (period 1), the patients received total parenteral nutrition (TPN) with caloric intake adjusted to 130% of their baseline resting energy expenditure (REE) measured by indirect calorimetry. Baseline REE was determined on the date of admission. The TPN formulation consisted of 100 grams of fat (Intralipid 20%, Kabi-Vitrum Labs, Inc.), 200 grams of carbohydrate (dextrose, 20%), 114 grams of protein (Novamine, Kabi-Vitrum Laboratories, Inc.), one ampule of vitamins (M.V.C. 9+3, Lyphomed, Inc.), and one ampule of trace elements (TMA, Abbott Laboratories, Inc.), administered in an amount calculated to 130 times the baseline REE per day. The caloric intake was distributed as follows: 47% fat, 32% carbohydrates and 21% protein; the calorie to nitrogen ratio (Kcal:gm) was about 114:1.
On the next thirty days (period 2), TPN plus recombinant biosynthetic human growth hormone (hGH) were simultaneously administered subcutaneously, the hGH being administered at a dose of 30 ug/kg/day.
On the next thirty days (period 3), TPN alone was administered to the patients in the same amounts as given in period 1.
Balance measurements Intakes of each nutrient were calculated from differences in weights of full and used containers, and the composition specifications. 24 hour urine collections were analyzed for total nitrogen, urea and creatinine. Total mtrogen was determined by chemiluminescence using a Model 703C Analyzer (Antek Instruments, Inc., Houston, Texas). Nitrogen balance was calculated from the difference between nitrogen intake and urinary excretion. In order to approximate the nitrogen content of stool and integumental losses, a correction factor of 14.6 mg of nitrogen/kg body weight was added. A random stool sample was also analyzed to confirm this range. The daily nitrogen balance was corrected for changes in plasma urea, assuming that urea was evenly distributed throughout body water. Total body water was estimated from regression equations relating to age, sex and weight. In order to estimate steady state conditions in each of the thirty day periods studied, the first two days were disregarded. IGF-1 concentration Blood was collected in EDTA ("Lavender") tubes and plasma was
separated by centrifugation. Plasma was placed in polypropylene tubes and rapidly cooled to 0°C. IGF-1 levels were measured by radioimmunoassay by a commercial reference lab (MetPath).
Before the administration of growth hormone (period 1), baseline IGF-1 plasma levels were between 65.8 ng/ml and 213.8 ng/ml (mean = 138). After the administration of growth hormone (period 2), IGF-1 levels rose to between 63.9 ng/ml and 749.3 ng/ml of plasma (mean = 300), as shown in FIG. 1. These results demonstrate that, contrary to the standard teaching that IGF-1 levels do not respond to admimstration of hGH, AIDS patients will respond to the admimstration of hGH with an increase in IGF-1 levels.
Nitrogen balance During TPN admimstration in period 1, nitrogen balance was 4.05 g/day, as shown in FIG. 2. Nitrogen increased to 11.13 g/day with the addition of hGH in period 2. This effect diminished in period 3 and returned to a baseline level of 4.35 g/day.
The effect of growth hormone on energy expenditure eventually brought the patients to near-zero energy balance. This reduction in energy balance due to hGH would normally be expected to adversely affect nitrogen balance. However, the addition of hGH produced a surprising and beneficial increase in nitrogen balance in spite of the reduction in energy balance.
With TPN alone it is expected that a steady state nitrogen balance will occur by day 4 of administration of TPN. Corrected nitrogen balance increased significantly when hGH was administered to the patient in addition to TPN. Thus, the increase in nitrogen balance represents an effect attributable to continuing exposure to hGH.
Although energy balance decreased and nitrogen intake was stable, the observed nitrogen balance significantly increased in period 2 and was a larger increase than would have been expected when TPN alone is admimstered to the patient. These results demonstrate the strong effect that hGH has on nitrogen balance and suggest that hGH may lower the optimum Kcal/nitrogen ratio.
Fuel oxidation Fat oxidation was 49.02 g/day during period 1, as shown in FIG. 3. With the addition of hGH it rose to 71.5 g/day in period 2. This increase in fat oxidation persisted in period 3 at 69.6 g/day, suggesting a persistent hGH effect.
Carbohydrate oxidation was 297.9 g/day in period 1 and decreased when hGH was added in period 2 to 217.65 g/day, as shown in FIG 4. Carbohydrate oxidation returned closer to baseline range in period 3 to 250.8 g/day, but not completely, again suggesting a prolonged hGH induced metabolic effect.
In FIG. 5, protein oxidation was 48.52 g/day in period 1. With the addition of hGH in period 2, protein oxidation decreased to 43.8 g/day. Protein oxidation returned to baseline levels of 50 g/day in period 3. The effects of hGH on fuel metabolism were more prolonged with regard to fat and carbohydrate oxidation than with protein oxidation. This is also reflected by the nitrogen balance data. Both protein oxidation and nitrogen balance returned to baseline in period 3, whereas, fat and carbohydrate oxidation did not completely return to baseline levels in period 3. Unexpectedly, the increase in fat oxidation persisted after administration of hGH was stopped, representing a novel and unique effect of hGH which
has not been previously demonstrated.
Free fatty acids Free fatty acids increased from 242.5 microequivalents/1 in period 1 to 244.74 microequivalents/1 in period 2. In period 3, free fatty acid levels declined to 154.9 microequivalents/1.
Energy expenditure, substrate utilization
As expected, the addition of hGH elevated REE from 1637.8 to 1775.5 Kcal/day. This data points out the need of using hGH in conjunction with nutritional support in persons with AIDS or AIDS-related diseases who are already hypermetabolic to avoid inducing a severe negative energy balance. Oxygen utilization (VO2) increased and the respiratory quotient (RQ) declined when hGH was co-administered with TPN.
FIGS. 3 to 5 demonstrate the beneficial metabolic changes produced when human growth hormone is administered in addition to TPN. FIG. 3 compares fat oxidation and balance during each of the three periods in the study. During period 1 there is a positive fat balance and positive fat oxidation. However, upon addition of human growth hormone to TPN in period 2 fat oxidation increased and fat balance declined. This effect persisted into period 3. This is beneficial since it indicates that more energy is being derived from the metabolism of fat. FIG. 4 demonstrates that a positive carbohydrate balance is achieved through the addition of human growth hormone to TPN. During period 1, there is a negative carbohydrate balance. However, upon administration of human growth hormone
in addition to TPN, in period 2, carbohydrate balance is less negative when compared to TPN alone. There is a trend to a return in the direction of period 1 in period 3. This is beneficial since there is decreased carbohydrate oxidation with concomitant decreased production of CO2.
FIG. 5 demonstrates the decreased protein oxidation and increased protein balance achieved though the administration of human growth hormone with TPN. During period 1, there is a positive protein balance. Upon administration of human growth hormone in period 2, protein balance increases even further. A return to pre-hGH
protein balance levels is observed in period 3.
The data on substrate oxidation and balance show enhanced fat metabolism
and reduced utilization of carbohydrates. Lipogenesis induced by TPN was progressively reduced when hGH was added, eventually changing to lipolysis. Carbohydrate oxidation decreased, producing glycogen storage by the end of period 2. Protein oxidation decreased in accordance with the protein sparing effect of hGH. IGF-1 levels rose to levels about 160 ng/ml or more than 200% of the baseline IGF-1 levels.
When compared to patients treated with TPN alone, patients receiving hGH and TPN had less carbohydrate oxidation, more fat oxidation and a higher positive nitrogen balance. These results show that treatment of persons with AIDS or AIDS- related diseases by the simultaneous treatment of hGH and TPN stimulates nutritional repletion without increasing metabolic demands or respiratory quotient.
* * * * * *
The above description is meant to be illustrative of the present invention, and not limiting thereof. All explanations of the inventor's theory of the invention are for illustrative purposes only. It is the inventor's intention that the scope of his invention be
defined solely by the following claims.

Claims

1. A nutrient formulation for a person with AIDS or AIDS-related
diseases, which comprises in combination:
(a) a metabolically active peptide exhibiting the metabolic effects associated with human growth hormone selected from the group consisting of human growth hormone, human growth hormone releasing factor, somatomedins, and mixtures thereof in
an amount which is sufficient to increase the person's baseline circulating IGF-1 levels
from 40% to 400%; and
(b) a nutritional supplement in an amount providing a daily caloric intake from 100 to 200% of the person's baseline resting energy expenditure, said nutritional supplement providing from 300 g to 700 g carbohydrate per day.
2. The formulation of claim 1, wherein the human growth hormone is recombinant human growth hormone and the amount is from 30 μg to 50 μg of the recombinant human growth hormone per kilogram of the person's body weight per day.
3. The formulation of claim 1, wherein the human growth hormone is incorporated in a time release dosage.
4. The formulation of claim 1, wherein the nutritional formulation further comprises fats in an amount of from 30 to 70% of the total caloric content.
5. The formulation of claim 1, wherein the nutritional formulation further comprises proteins in an amount of 10 to 30% of the total caloric content.
6. The formulation of claim 1, wherein the nutritional formulation further comprises vitamins, electrolytes, and mineral micronutrients.
7. A nutrient formulation for use in the treatment of malnutrition in a person with AIDS or AIDS-related diseases, which comprises in combination: (a) a metabolically active peptide exhibiting the metabolic effects associated with human growth hormone selected from the group consisting of human growth hormone, human growth hormone releasing factor, somatomedins, and mixtures thereof in an amount which is sufficient to increase the person's baseline circulating IGF-1 levels from 40% to 400%; and
(b) a nutritional supplement in an amount providing a daily caloric intake from 100 to 200% of the person's baseline resting energy expenditure, said nutritional supplement providing from 300 g to 700 g carbohydrate per day.
8. The formulation of claim 7, wherein the human growth hormone is recombinant human growth hormone and the amount is from 30 μg to 50 μg of the recombinant human growth hormone per kilogram of the person's body weight per day.
9. The formulation of claim 7, wherein the human growth hormone is incorporated in a time release dosage.
10. The formulation of claim 7, wherein the nutritional formulation further comprises fats in an amount of from 30 to 70% of the total caloric content.
11. The formulation of claim 7, wherein the nutritional formulation further comprises proteins in an amount of 10 to 30% of the total caloric content.
12. The formulation of claim 7, wherein the nutritional formulation further comprises vitamins, electrolytes, and mineral micronutrients.
13. A method for treating malnutrition in persons with AIDS or AIDS- related diseases, which comprises concurrently administering to the person: a) a metabolically active peptide exhibiting the metabolic effects associated with human growth hormone selected from the group consisting of human growth hormone, human growth hormone releasing factor, somatomedins, and mixtures thereof, in an amount sufficient to increase circulating IGF-1 levels from 40% to 400%
above the person's baseline plasma IGF-1 level; and
b) a nutritional supplement, in an amount providing a daily caloric intake in the range of from 100 to 200 % of the person's resting energy expenditure (REE), said supplement providing at least 300 grams of carbohydrate per day.
14. The method of claim 13, wherein the daily caloric intake in said
supplement is from 130 to 170% of the person's baseline REE.
15. The method of claim 13, wherein the metabolically active peptide is recombinant human growth hormone, the human growth hormone is adn inistered subcutaneously in an amount of between 30 ug/kg/day and 50 ug/kg/day, and the nutritional supplement is admimstered parenterally.
16. The method of claim 13, wherein the metabolically active peptide is adrninistered in a time release formulation.
17. The method of claim 13, wherein the nutritional supplement further comprises fats in an amount of 30 to 70% of the daily caloric intake.
18. The method of claim 13, wherein the nutritional supplement further comprises fats in an amount of 10 to 30% of the daily caloric intake.
19. The method of claim 13, wherein the nutritional supplement further comprises vitamins, electrolytes, and mineral micronutrients.
20. The method of claim 13, wherein the human growth hormone is recombinant human growth hormone.
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