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WO1996002270A1 - Utilisation du facteur de croissance semblable a l'insuline et combine a l'insuline - Google Patents

Utilisation du facteur de croissance semblable a l'insuline et combine a l'insuline Download PDF

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Publication number
WO1996002270A1
WO1996002270A1 PCT/AU1995/000422 AU9500422W WO9602270A1 WO 1996002270 A1 WO1996002270 A1 WO 1996002270A1 AU 9500422 W AU9500422 W AU 9500422W WO 9602270 A1 WO9602270 A1 WO 9602270A1
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WO
WIPO (PCT)
Prior art keywords
insulin
igf
growth factor
administered
day
Prior art date
Application number
PCT/AU1995/000422
Other languages
English (en)
Inventor
Francis Mathew Tomas
Allan Malcolm Rofe
Francis John Ballard
Original Assignee
Gropep Pty. Ltd.
Medvet Science Pty. Ltd.
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 Gropep Pty. Ltd., Medvet Science Pty. Ltd. filed Critical Gropep Pty. Ltd.
Priority to AU29174/95A priority Critical patent/AU2917495A/en
Publication of WO1996002270A1 publication Critical patent/WO1996002270A1/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
    • A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2

Definitions

  • This invention relates to the combined use of insulin-like growth factor and insulin in promoting growth, treating catabolic diseases including but not limited to cancer, and enhancing wound repair.
  • the invention also relates to pharmaceutical and veterinary compositions useful for promoting growth, treating catabolic diseases and enhancing wound repair.
  • IGF-II insulin-like growth factor-I and IGF-II share considerable sequence homology as indicated from their names. Nevertheless, insulin acts through a distinct receptor which has a low affinity for IGF-I or IGF-II, whereas IGF-I and IGF-II are considered to elicit their growth-stimulating responses through the type 1 IGF receptor.
  • the two growth-related receptors are distributed in mammals in a tissue-specific manner so that the insulin receptor is abundant in adipose tissue, liver and muscle while the type 1 IGF receptor has a high density especially in muscle, kidney and gut tissues but is absent in the parenchynal cells of liver and is barely detectable in adipose tissue.
  • Insulin, IGF-I and IGF-II all produce short-term metabolic effects and longer-term growth responses in their target tissues. Since the clinical importance of insulin is mostly associated with metabolic responses such as uptake of glucose and amino acids from blood, the inhibition of gluconeogensis or the promotion of lipid deposition through increases in lipogenesis and decreases in lipolysis, longer-term growth responses have sometimes been suggested to occur via the limited cross-reactivity of insulin with the type 1 IGF receptor. The opposite situation with the IGFs has also been proposed with their short-term metabolic effects postulated to occur through the insulin receptor. However, a number of investigations have been reported in which subjects, animals or cells with insulin resistance demonstrate normal responsiveness to IGF-I that includes short-term metabolic effects. Examples of these reports include T.
  • the prior art also contains many examples whereby IGF can promote bod weight gain and improve nitrogen balance or retard weight loss in rats that are n diabetic. Examples include normal animals (F.M. Tomas et al. J. Endocrinol. 13
  • IGF administration to human subjects with catabolic diseases generally leads only to transient increase in circulating IGF-I and only a transient improvement i nitrogen balance or weight gain (S.A. Chen et al. 75th Ann. Meeting. Endocrino
  • a method for the treatment of catabolic diseases in mammals including the step of administering to the mammal an effective amount of: insulin-like growth factor (IGF), and insulin.
  • IGF insulin-like growth factor
  • insulin as used herein includes both the natural and recombinantly produced pancreatic hormone.
  • the term includes all mammalian sequences of the hormone and is limited only in that the material must demonstrate the expected biological activity of the hormone in the recipient. Therefore the term also applies to analogues of any mammalian insulin provided they are physiologically reactive.
  • IGF insulin-like growth factor
  • IGF-I insulin-like growth factor-l
  • IGF-II insulin-like growth factor-ll
  • the term includes all mammalian sequences of IGF-I and IGF-II. The term is limited only in that the material must demonstrate IGF activity in the recipient.
  • an effective amount refers to amounts of insulin-like growth facto (IGF) and insulin, or sources thereof, capable of inducing the desire pharmaceutical or veterinary effect.
  • IGF insulin-like growth facto
  • the active ingredients are suspended, dissolved or dispersed i a carrier.
  • the carrier may be any solid or liquid that is non-toxic to the mamma and compatible with the active ingredient.
  • Suitable carriers include liquid carrier such as normal saline and other non-toxic salts at or near physiologica concentrations and dilute acids. Other forms such as aerosols or slow releas pellets are also contemplated.
  • the combined treatment of the invention is also useful in promoting growth in mammals.
  • a method for promoting growth in a mammal including the step of administering to the mammal an effective amount of: insulin-like growth factor (IGF), and insulin.
  • IGF insulin-like growth factor
  • the invention also provides a pharmaceutical or veterinary composition including effective amounts of: insulin-like growth factor (IGF), and insulin.
  • IGF insulin-like growth factor
  • the compositions of the invention may further include a pharmaceutically or veterinarily acceptable diluent, carrier or excipient therefore.
  • the particular carrier or excipient employed will depend necessarily on the method of administration and could be readily chosen by a person skilled in the art.
  • mammal as used herein is intended to include, but is not limited to, human subjects, pigs, cattle, sheep, guinea pigs and rodents.
  • catabolic disease As used herein, the terms “catabolic disease”, “catabolic states” and “catabolic conditions” are intended to describe wasting conditions that include but are not limited to, cancer, acute or chronic organ failure, AIDS, physical trauma, infection and anorexia. Diabetes is specifically excluded.
  • compositions of the present invention are expected to enhance wound repair in mammals.
  • the invention further provides a method for enhancing wound repair in a mammal including the step of administering to the mammal an effective amount of: insulin-like growth factor (IGF), and insulin.
  • IGF insulin-like growth factor
  • the present invention is the first to combine the use of insulin with IGF for the treatment of catabolic diseases or to promote growth. Specifically, growth can be promoted or catabolic diseases can be reversed or ameliorated by the administration of insulin in combination with an insulin-like growth factor (IGF).
  • IGF insulin-like growth factor
  • the present invention discloses the unexpected result that insulin and IGF act synergistically to reverse the catabolic state. Without wishing to be limited by theory it is believed that this synergis partly occurs through the restoration of food intake in experimental animals by t added insulin which in turn provides the nutrients required to reverse tiss catabolism.
  • the present invention also discloses that the unexpected synergis between IGF and insulin leads to a more balanced reversal of the catabolic sta in which insulin predominantly increases growth of muscle as well as f deposition, while IGF predominantly increases the growth of certain non-carca tissues such as those of the gastrointestinal tract.
  • gut disease refers to digestive or absorptive disorders of a region of the gastrointestinal tract as well as inflammatory bowel diseases a mucositis.
  • the invention further provides a method for treating gut disea including the step of administering to a mammal an effective amount of: insulin-like growth factor (IGF), and insulin.
  • IGF insulin-like growth factor
  • the materials of the present invention may be administered by any mea or pharmaceutical compositions that achieve their intended purpose.
  • administration of the materials of the present invention may be subcutaneous, intravenous, intramuscular, intraperitoneal or transdermal routes.
  • the amount of IGF administered to the mammal will depend on the type mammal, the age, health status and weight of the recipient, the mode administration and frequency of treatment, whether IGF-I, IGF-II or an IGF analogue is the chosen material, and the concurrent insulin treatment selected. Generally a daily dosage of IGF from 0.01 to 5.0 mg/kg body weight is effective.
  • the amount of insulin administered to the mammal will depend on the type of mammal, the age, health status and weight of the recipient, the mode of administration and frequency of treatment, and the concurrent IGF treatment selected. Generally a daily dosage of insulin from 0.01 to 2.0 mg/kg body weight is effective.
  • the insulin and IGF are administered over a period of between 1 and 60 days.
  • the sources of insulin-like growth factor and insulin may be administered to the mammal as a composition which includes the IGF and insulin, or the IGF and insulin may be administered to the mammal separately.
  • the IGF may be administered at the same time as, before or after the administration of the insulin.
  • the invention provides a kit for treating a catabolic disease promoting growth, enhancing wound repair or treating gut disease in a mammal, said kit including:
  • composition including insulin and a pharmaceutically or veterinarily acceptable diluent, carrier or excipient therefor, and
  • IGF insulin-like growth factor
  • the kit may further include means for administering components (a) and
  • the methods and compositions of the present invention for enhancin growth in a mammal are suitable for the treatment of different species and different developmental stages.
  • the combined insulin and IG treatment may be used in suckling pigs or at the finisher stage.
  • compositions of the present invention for treatin catabolic conditions are suitable for a wide range of such states.
  • th combined insulin plus IGF treatment may be used in cancer-bearing subjects experimental animals, in conditions of acute or chronic organ failure, in physic trauma or prolonged infection. Since the methods of the invention are directed the catabolic state and not to the condition itself, the methods and compositio are expected to be capable of being utilized to treat all conditions resulting i catabolic states.
  • Examples 1 to 4 described below illustrate the use of the combinatio treatment of the present invention to restore host weight gain in tumour-bearin rats. In the absence of treatment this example shows body weight gain over a day period, but all the weight gain is tumour.
  • Insulin alone produces a modest increase in tumour-free body weight an enhances food intake.
  • IGF has little effect on tumour-free body weight but inhibit food intake.
  • a synergistic response is evident when insulin and IGF are c administered, since the improved food intake licited by insulin alone is maintaine while the tumour-free body weight gain is substantially greater.
  • the synergy i also evident in the distribution of retained nitrogen in the tissues of the hos Specifically, insulin alone increases growth of the muscle, skeleton and fat components that make up the carcass, IGF stimulates growth of non-carcass tissues, while the combination treatment produces balanced growth of the carcass and non-carcass body components.
  • plasma insulin concentrations are depressed by the administration of IGF alone.
  • Insulin and IGF-I have differential effects on the individual organs.
  • insulin but not IGF-I increases fat stores and skin weight but decreases spleen weight and tends to decrease kidney weight; IGF-I increases spleen, kidney and gut weights and decreases the weight of fat stores, while the combination treatment produces the desired increases in all tissues.
  • mice Female Dark Agouti rats (180 g body wt.) were held in cages at 25°C under controlled lighting (12 h-dark 12h-light cycle). The rats were fed on a commercial chow diet prior to implantation with a mammary adenocarcinoma. After implantation by subcutaneous injection of a cell suspension into each flank the tumour grows to 15% of host body weight in 2-3 weeks (A. Rofe et al. Biochem. J. 233, 485, 1986). Experiments were conducted over a 6 or 7 day period, during which time the tumour normally grows from 5% to 15% of body wt. Six rats were included in each experimental group. When the tumour had grown to 5% of body weight, as assessed by calliper measurement, mini-osmotic pumps containing the appropriate materials were implanted subcutaneously in the supra- scapular region.
  • Insulin 100 19.0+0.5 *** 19.1 ⁇ 1.7 *** 110+8 115 ⁇ 6 **
  • Insulin and the IGF analogue LR IGF-I produced distinct responses. Insulin significantly stimulated fo intake, tumour-free body weight gain and reduced the tumour burden, whi LR 3 IGF-I improved nitrogen balance, increased tumour burden and slightly decreased food intake.
  • the combination treatment of insulin plus LR 3 IGF-I synergistically increased the tumour-free body weight gain and the nitrogen balance well above the individual treatment values, while the tumour burden was unchanged from the control group. Accordingly this experiment demonstrates the usefulness of the combination treatment in the catabolic state induced by a rapidly growing tumour.
  • tumour free nitrogen gain in the combined treatment was significantly gre (p ⁇ 0.001) than the gain in either the insulin-treated or the IGF-treated gro Surprisingly, however, all the gain produced by insulin was in carcass tiss while all the gain produced by IGF-I was in non-carcass tissues.
  • the combi treatment produced approximately equal increases in the carcass and n carcass nitrogen.
  • Example 2 This experiment was carried out as described in Example 1 except that dosage of insulin was reduced by one half to 50 ⁇ g/rat/day and the dosage LR 3 IGF-I was reduced by one quarter to 150 ⁇ g/rat/day. In addition, no tiss were discarded and nitrogen accumulation was directly measured in all tissues.
  • the measurements in this example are the organ weights obtained when the experimental animals in Examples 2 and 3 were killed. Weights are expressed as grams wet weight of tissue per kilogram of body weight after the tumour weight had been subtracted. * P ⁇ 0.05 versus respective vehicle groups for increases in tissue weight; + P ⁇ 0.05 versus respective vehicle groups for decreases in tissue weight.
  • kidney weights tend to be lower in insulin-treated animals (not statistically significant) but are significantly higher in LR 3 IGF-l-treated and combination-treated animals;
  • spleen weights are lower in insulin-treated rats but are higher in IGF-l-treated and combination-treated rats;
  • Omental fat, measured only in Example 3 was substantially reduced in LR 3 IGF-I -treated animals but restored to normal when insulin was included with LR 3 IGF-I;
  • Example 3 the skin (pelt) weight was increased by insulin and the combined treatment; a similar but non-significant trend occurred in Example 2;
  • the weight of the empty gut was unaffected by insulin but substantially increased in the LR 3 IGF-l-treated and combination-treated groups.

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

Abstract

L'invention concerne un procédé de traitement de maladies cataboliques autres que le diabète, favorisant la croissance, améliorant la cicatrisation ou traitant des maladies intestinales chez un mammifère et consistant à administrer des quantités effectives du facteur de croissance semblable à l'insuline (IGF) et de l'insuline. L'invention concerne également des compositions pharmaceutiques et vétérinaires et des kits pour traiter ces états.
PCT/AU1995/000422 1994-07-13 1995-07-13 Utilisation du facteur de croissance semblable a l'insuline et combine a l'insuline WO1996002270A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU29174/95A AU2917495A (en) 1994-07-13 1995-07-13 Use of insulin-like growth factor in combination with insulin

Applications Claiming Priority (2)

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AUPM6782 1994-07-13
AUPM6782A AUPM678294A0 (en) 1994-07-13 1994-07-13 Use of insulin-like growth factor in combination with insulin

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998006423A1 (fr) * 1996-08-13 1998-02-19 Genentech, Inc. Composition contenant de l'insuline et le facteur de croissasnce de substances apparentees a l'insuline (igf-i)
US5868728A (en) * 1995-02-28 1999-02-09 Photogenesis, Inc. Medical linear actuator for surgical delivery, manipulation, and extraction
US5994303A (en) * 1994-07-01 1999-11-30 Chiron Corporation Use of insulin and IGF-I
WO2001000223A2 (fr) * 1999-06-25 2001-01-04 Minimed Inc. Therapie anti diabete a agents multiples
GB2369572A (en) * 2000-11-29 2002-06-05 Raft Trustees Ltd Wound treatment composition comprising insulin
US6737401B2 (en) 2001-06-28 2004-05-18 Metronic Minimed, Inc. Methods of evaluating protein formulation stability and surfactant-stabilized insulin formulations derived therefrom
US6852694B2 (en) 2001-02-21 2005-02-08 Medtronic Minimed, Inc. Stabilized insulin formulations
US7749966B2 (en) * 2006-12-21 2010-07-06 Boston Biomedical Research Institute Immunological modulation of insulin-like growth factor 1 for cancer prevention/treatment and prolonging longevity
WO2010109239A1 (fr) 2009-03-27 2010-09-30 First Water Limited Compositions multicouches et pansements
WO2015059501A1 (fr) 2013-10-24 2015-04-30 First Water Limited Pansements hydrogel souples pour plaies
US9056127B2 (en) 2008-01-17 2015-06-16 First Water Limited Hydrogel composition based on co-polymer carrying multiple pendant sulphonic groups for use as a wound dressing

Citations (9)

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Publication number Priority date Publication date Assignee Title
AU5790890A (en) * 1989-06-29 1991-01-03 University Of Dundee, The Hair growth composition
WO1992020367A1 (fr) * 1991-05-24 1992-11-26 Amylin Pharmaceuticals, Inc. Traitement de l'anorexie et des pathologies voisines
WO1993000110A1 (fr) * 1991-06-28 1993-01-07 Genentech, Inc. Procede de stimulation de la reponse immunitaire
JPH0543453A (ja) * 1991-08-20 1993-02-23 Sumitomo Pharmaceut Co Ltd 創傷治癒促進用局所用徐放性製剤
WO1993004691A1 (fr) * 1991-08-30 1993-03-18 Life Medical Sciences, Inc. Composition et procede de traitement de blessures
WO1993010806A1 (fr) * 1991-11-25 1993-06-10 Institute Of Molecular Biology, Inc. Medicament servant a la promotion de la croissance d'un nerf chez les mammiferes
EP0561330A1 (fr) * 1992-03-17 1993-09-22 Pharmed Dr. Liedtke Gmbh Préparation topique contenant de l'insuline
WO1994004030A1 (fr) * 1992-08-26 1994-03-03 Celtrix Pharmaceuticals, Inc. Procede de traitement systemique d'etats cataboliques et de lesions tissulaires systemiques
WO1994016723A2 (fr) * 1993-01-29 1994-08-04 Synergen, Inc. Composition de cicatrisation de plaies

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5790890A (en) * 1989-06-29 1991-01-03 University Of Dundee, The Hair growth composition
WO1992020367A1 (fr) * 1991-05-24 1992-11-26 Amylin Pharmaceuticals, Inc. Traitement de l'anorexie et des pathologies voisines
WO1993000110A1 (fr) * 1991-06-28 1993-01-07 Genentech, Inc. Procede de stimulation de la reponse immunitaire
JPH0543453A (ja) * 1991-08-20 1993-02-23 Sumitomo Pharmaceut Co Ltd 創傷治癒促進用局所用徐放性製剤
WO1993004691A1 (fr) * 1991-08-30 1993-03-18 Life Medical Sciences, Inc. Composition et procede de traitement de blessures
WO1993010806A1 (fr) * 1991-11-25 1993-06-10 Institute Of Molecular Biology, Inc. Medicament servant a la promotion de la croissance d'un nerf chez les mammiferes
EP0561330A1 (fr) * 1992-03-17 1993-09-22 Pharmed Dr. Liedtke Gmbh Préparation topique contenant de l'insuline
WO1994004030A1 (fr) * 1992-08-26 1994-03-03 Celtrix Pharmaceuticals, Inc. Procede de traitement systemique d'etats cataboliques et de lesions tissulaires systemiques
WO1994016723A2 (fr) * 1993-01-29 1994-08-04 Synergen, Inc. Composition de cicatrisation de plaies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PATENT ABSTRACTS OF JAPAN, C-1076, page 159; & JP,A,05 043 453 (SUMITOMO PHARMACEUT CO LTD), 23 February 1993. *

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5994303A (en) * 1994-07-01 1999-11-30 Chiron Corporation Use of insulin and IGF-I
US5868728A (en) * 1995-02-28 1999-02-09 Photogenesis, Inc. Medical linear actuator for surgical delivery, manipulation, and extraction
US5783556A (en) * 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
EP1114644A1 (fr) * 1996-08-13 2001-07-11 Genentech, Inc. Composition comportant NPH insuline (neutre protamine insuline de Hagedorn)
WO1998006423A1 (fr) * 1996-08-13 1998-02-19 Genentech, Inc. Composition contenant de l'insuline et le facteur de croissasnce de substances apparentees a l'insuline (igf-i)
WO2001000223A2 (fr) * 1999-06-25 2001-01-04 Minimed Inc. Therapie anti diabete a agents multiples
WO2001000223A3 (fr) * 1999-06-25 2001-05-25 Minimed Inc Therapie anti diabete a agents multiples
US7323543B2 (en) 1999-06-25 2008-01-29 Minimed, Inc. Multiple agent diabetes therapy
US8557770B2 (en) 2000-11-29 2013-10-15 Pharmecosse Ltd. Method of preventing or reducing scarring of human skin
GB2369572A (en) * 2000-11-29 2002-06-05 Raft Trustees Ltd Wound treatment composition comprising insulin
US9308240B2 (en) 2000-11-29 2016-04-12 Pharmecosse Limited Method of preventing or reducing scarring of human skin
US6852694B2 (en) 2001-02-21 2005-02-08 Medtronic Minimed, Inc. Stabilized insulin formulations
US6737401B2 (en) 2001-06-28 2004-05-18 Metronic Minimed, Inc. Methods of evaluating protein formulation stability and surfactant-stabilized insulin formulations derived therefrom
US7749966B2 (en) * 2006-12-21 2010-07-06 Boston Biomedical Research Institute Immunological modulation of insulin-like growth factor 1 for cancer prevention/treatment and prolonging longevity
US9056127B2 (en) 2008-01-17 2015-06-16 First Water Limited Hydrogel composition based on co-polymer carrying multiple pendant sulphonic groups for use as a wound dressing
WO2010109239A1 (fr) 2009-03-27 2010-09-30 First Water Limited Compositions multicouches et pansements
US8871992B2 (en) 2009-03-27 2014-10-28 First Water Limited Multilayer compositions and dressings
WO2015059501A1 (fr) 2013-10-24 2015-04-30 First Water Limited Pansements hydrogel souples pour plaies
US10688215B2 (en) 2013-10-24 2020-06-23 First Water Limited Flexible hydrogel wound dressings

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