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WO1995007711A1 - Traitement therapeutique destine a inhiber l'obstruction des vaisseaux sanguins a l'aide d'un polypeptide - Google Patents

Traitement therapeutique destine a inhiber l'obstruction des vaisseaux sanguins a l'aide d'un polypeptide Download PDF

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Publication number
WO1995007711A1
WO1995007711A1 PCT/US1994/010381 US9410381W WO9507711A1 WO 1995007711 A1 WO1995007711 A1 WO 1995007711A1 US 9410381 W US9410381 W US 9410381W WO 9507711 A1 WO9507711 A1 WO 9507711A1
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WIPO (PCT)
Prior art keywords
vascular
following
during
therapeutic
procedure
Prior art date
Application number
PCT/US1994/010381
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English (en)
Inventor
Daniel Burleigh
Original Assignee
Mallinckrodt Medical, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to EP94927421A priority Critical patent/EP0722334A1/fr
Priority to JP7509330A priority patent/JPH09502726A/ja
Priority to AU76871/94A priority patent/AU7687194A/en
Publication of WO1995007711A1 publication Critical patent/WO1995007711A1/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
    • A61K38/2221—Relaxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy

Definitions

  • This invention relates generally to a novel use of a polypeptide hormone for therapeutic use, and more particularly, to novel methods of using the hormone Relaxin, and to pharmaceutical compositions comprising the hormone Relaxin for novel therapeutic use in preventing or minimizing arterial cell injury and proliferation during and following angioplasty procedures.
  • Balloon angioplasty, atherectorry, rotorary ablation and similar therapeutic techniques, collectively called angioplasty, are used to improve circulation in vivo and are finding ever-increasing application in therapeutic cardiology.
  • balloon angioplasty procedures involve the introduction of a balloon-type catheter into the narrowed portion of an artery.
  • the narrowing of the artery may be caused by different factors but most commonly is caused by a build-up of "atherosclerotic plaque", and proliferation of intimal and neointimal vascular smooth muscle cells.
  • the balloon portion of the catheter is inflated.
  • the inflation of the balloon within the narrowed area of the artery is intended to restore the diameter of the blood vessel thus improving circulation.
  • the present invention discloses a novel method of using a hormone, Relaxin, in balloon-type catheters for therapeutic treatment to prevent or minimize vascular restenosis.
  • Restenosis is a recurrent stenosis, i.e., a narrowing or stricture of a duct or canal. Restenosis and the development of atheromatous lesions (the reason for the procedure in the first place) are thought to share several common pathological elements such as the accumulation of monocytes and macrophages at the area of injury or inflammation and the proliferation of vascular smooth muscle.
  • Growth factors which induce this proliferation of vascular smooth muscle cells thus causing restenosis may arise from initial platelet lysis and/or from many other cellular elements, including the monocytes and macrophages which infiltrate the injured area in response to the inflammatory stimuli.
  • the stimuli which give rise to the proliferation of smooth muscle and other cells are thought to be triggered in part by the trauma of the procedure itself.
  • the greater the severity of the procedure needed to open the artery the greater the probability of a more vigorous proliferative process and attendant restenosis.
  • the hormone Relaxin is a small globular protein of the insulin super-family. Among its many actions, Relaxin acts upon smooth muscle cells to suppress contraction in response to other stimuli, and to relax contractile elements within the cell, allowing stretching beyond limits that normally would cause cellular injury and tissue damage in the absence of the hormone. Indeed, an important physiological function of Relaxin is to cause the relaxation of smooth muscle cells within the cervix, allowing parturition without injury to the mother. Relaxin also acts to induce remodeling of the extracellular matrix, increasing elasticity of tissue in the area of its action, and increasing the limits of stretching and strain this tissue may be subjected to without cell disruption and destruction. In accordance with the present invention, local or systemic treatment of arterial atherosclerotic lesions with Relaxin prior to or concurrent with angioplasty procedures prevents or minimizes tissue damage, and consequent inflammation and restenosis responses.
  • a balloon-type catheter such as a balloon infusion catheter, hydrogel catheter, or stent
  • a composition containing the hormone Relaxin or a Relaxin containing composition may otherwise be incorporated into the particular delivery system of choice.
  • Relaxin is a small globular . protein comprising two polypeptide chains linked together with disulfide bridges which have the same disposition as those in insulin, and a tertiary structure closely resembling that of insulin.
  • the amino acid sequence for human Relaxin is as follows;
  • A represents Alanine
  • C represents Cysteine
  • D represents Aspartic Acid
  • E represents Glutamic Acid
  • F represents Phenylalanine
  • G represents Glycine
  • H represents Histidine
  • I represents Isoleucine
  • K represents Lysine
  • L represents Leucine
  • M represents Methionine
  • N represents Asparagine
  • P represents Proline
  • Q represents Glutamine
  • R represents Arginine
  • S represents Serine
  • T represents Threonine
  • V represents Valine
  • W represents Tryptophan
  • X represents an unspecified or variable amino acid
  • Y represents Tyrosine.
  • Relaxin acts by binding to specific cell surface receptors on those target cells which possess them. Relaxin has been shown to bind specifically to an increasingly diverse group of target cells. Examples of such target cells possessing Relaxin specific receptors include uterine myometrial cells, cervical smooth muscle cells, connective tissue fibroblasts of the pubic symphasis ligaments, intestinal epithelium, brain, and vascular smooth muscle cells. The surface receptors themselves are transmembrane proteins, and the binding of Relaxin thereto triggers a sequence of transduction events within the target cell which mediates pleiotropic actions. Relaxin receptors from rat ovary and rat brain have identical binding and biochemical properties as that of the human receptors indicating that the Relaxin receptor most likely is the same in all target cells.
  • Relaxin receptors have not been cloned and sequenced although biochemical evidence suggests that these receptors are symmetrical heterotetramers, incorporating an intracellular tyrosine kinase activity, and are probably members of the insulin - insulin like growth factor receptor family. This means that they are expected to act through the receptor tyrosine kinase transduction cascade.
  • Relaxin also acts as a tissue remodeling hormone. This means that Relaxin induces the synthesis and secretion of extracellular enzymes which catalyze the degradation and resorption of extracellular matrix proteins. Relaxin induces the replacement of the collagen matrix by elastin and loosens and increases the elasticity of target tissues. Relaxin also increases the degree tissues can be stressed and distended without cellular injury or disruption. Relaxin's specific binding, and tissue responsiveness to Relaxin have been observed in arterial vascular smooth muscle cells as described in G.N. Stemmerman, L. Tashima and F.C. Greenwood, Is Relaxin A Hormone Of The Human Gastrointestinal Epithelium?; Abstract #533, 75th Annual Meeting of the Endocrine Society, Las Vegas, NV 6/9-12/93.
  • Relaxin binding and effects on vascular smooth muscle cells allows an expectation of Relaxin efficacy in restenosis as follows: local delivery of Relaxin to hyperplastic medial and intimal smooth muscle cells within an atherosclerotic lesion, prior to or concurrent with angioplasty, will cause loosening of the extracellular matrix of the lesion, decreasing the trauma, cellular damage, and consequent inflammatory responses which trigger and drive restenosis. Continued controlled local delivery at the lesion site after angioplasty will promote a normal rather than hyperplastic wound-healing response, allowing a better outcome for the interventional procedure.
  • PTCA Percutaneous Transluminal Coronary Angioplasty
  • a therapeutically effective amount of the Relaxin polypeptide, a Relaxin mimic, or a molecule having similar receptor binding specificity, or a gene specifying coding or specifying the same may be administered to a warm-blooded animal .in vivo using a local delivery device incorporated into a balloon infusion catheter or a like delivery device of choice for delivery to the particular target site to thus minimize cell damage and subsequent restenosis which would require further interventional therapeutic action and could possibly be life-threatening.
  • the preferred embodiment of the present invention is the peptide, polypeptide or protein Relaxin or derivatives thereof used alone or in combination to prevent cellular damage during invasive therapeutic treatment of vascular stenosis.
  • Example 1 Demonstration of Relaxin Specific Binding to Receptors on Porcine Coronary Artery Smooth Muscle Cells In Monolayer Culture.
  • Porcine Coronary Artery Smooth Muscle Cells are grown to confluent monolayers in six (6) well cluster plates of 35 mm diameter (9.62 cm2) wells. The wells are then washed with binding buffer, e.g., 10 mM HEPES, 5mM KH 2 P0 4 , 5mM MgCl 2 , 150 mM NaCl, 1.0% (w/v) BSA (bovine serum albumin, RIA grade), 10 ug/ml Gentamycin, pH 7.4, and stabilized in the binding buffer for approximately 30 minutes at 22° C.
  • binding buffer e.g., 10 mM HEPES, 5mM KH 2 P0 4 , 5mM MgCl 2 , 150 mM NaCl, 1.0% (w/v) BSA (bovine serum albumin, RIA grade), 10 ug/ml Gentamycin, pH 7.4, and stabilized in the binding buffer for approximately 30 minutes at 22° C.
  • the wells are then incubated in triplicate with 1.0 ml of binding buffer containing 125-I-Relaxin, alone or with a specified dose of unlabeled Relaxin and incubated for approximately 30 minutes at 22° C. After incubation, the binding buffer is removed, and the wells are washed twice with 1 ml portions of ice-cold binding buffer.
  • the Smooth Muscle Cells in each well are then solubilized by dissolving the cells in 1.0 ml of solubilizing solution, e.g., 2.0 N NaOH in distilled water, which is transferred, with a 1.0 ml wash of the same stabilizing solution to a 12 x 75 mm counting tubes. Tubes are then counted in a gamma counter, and the Relaxin binding affinity and capacity are determined from this data.
  • Example 2 Immunohistochemical Detection of Specifically Bound Relaxin On Porcine Coronary Artery Smooth Muscle Cells.
  • Porcine Coronary Artery Smooth Muscle Cells are grown to confluent monolayers in complete culture medium (Dulbecco's Modified Eagle's Medium (DMEM) /10% FBS) on slide chambers.
  • the slide chambers are washed with binding buffer, and stabilized in the same buffer for 30 minutes at 25° C. (Binding Buffer: 10 mM HEPES, 5 mM KH 2 P0 4 , 5mM MgCl 2 , 150 mM NaCl, 1.0% (w/v) BSA., 10 ug/ml Gentamycin, pH 7.4).
  • the slide chambers are then incubated in binding buffer containing 1.0 ug/ml Relaxin, for 30 minutes at 25° C.
  • the slide chambers are washed two times with phosphate buffered saline (PBS) containing 0.2% BSA, and fixed for 20 minutes, at 25° C, in 4% paraformaldehyde in PBS, followed by two washings with PBS.
  • the fixative is quenched by incubation for 10 minutes at 25° C, in 50 mM NH 4 C1 in PBS and the slides are then washed twice with PBS and air-dried.
  • cell membranes are permeabilized by incubation for 10 minutes, at 25° C, with 0.2% Triton x-100 in PBS, followed by two washings with PBS.
  • the slide chambers are then incubated for 20 minutes at 25° C in blocking buffer, PBS containing 2.0% BSA, followed by three washings with PBS containing 0.2% BSA.
  • the slide chambers are then incubated with the primary antibody (rabbit anti-porcine relaxin) in binding buffer for 30 minutes at 25° C.
  • porcine relaxin at 1.0 ug/ml is added to some of the slide chambers during this incubation. All slide chambers are then washed three times with PBS containing 0.2% BSA.
  • the slide chambers are then incubated with the secondary antibody (fluorescein-conjugated goat anti-rabbit IgG) in binding buffer for 30 minutes at 25° C. All slide chambers are then washed twice with PBS containing 0.2% BSA., once with PBS, and once with distilled water.
  • the slides are then mounted with cover glasses and observed by epi- illumination fluorescence microscopy to detect specifically bound Relaxin.
  • Rats are placed under anesthesia and one carotid artery is exposed by an incision in the neck. A wound is then made in a marked neck segment of the rat carotid using either: a. Inflation of a balloon catheter in the marked segment, or B. repeated passage of a roughened length of suture material through the lumen of the marked segment.
  • an appropriate dose preferably between from 10.0 ng to 1.0 g of Relaxin in solution or suspension is delivered to the wounded arterial segment by appropriate means.
  • vehicle is similarly delivered.
  • the compound is may be used alone or with a pharmaceutically acceptable carrier in a method of performing therapy.
  • the preferred therapeutic procedure involves injecting or administering, for example by means of a balloon injector catheter, or other catheter-based delivery device, to a warm-blooded animal a therapeutically effective amount, usually within the range of 10.0 ng to 1.0 g of the present invention.
  • Pharmaceutically acceptable carriers for such therapeutic use include those that are suitable for injection or administration to a warm-blooded animal such as aqueous buffer solutions, e.g. tris (hydroxymethyl)aminomethane (and its salts) , chloride phosphate, citrate, bicarbonate, etc., sterile water for injection, physiological saline, and balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca + , Na + , K + and Mg 2+ .
  • aqueous buffer solutions e.g. tris (hydroxymethyl)aminomethane (and its salts) , chloride phosphate, citrate, bicarbonate, etc.
  • sterile water for injection physiological saline
  • balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca + , Na + , K + and Mg 2+ .
  • Other suitable buffer solutions are described in Remington's Practice of Pharmacy,
  • polymer-based controlled release delivery systems may also be used such as polylactic acid and derivatives thereof and/or polyethylene glylcol and its derivatives.
  • the concentration of the Relaxin peptide and the pharmaceutically acceptable carrier, for example in an aqueous medium, varies with the particular field of use.
  • a sufficient amount of Relaxin is present in the pharmaceutically acceptable carrier in the present invention when satisfactory effects on areas of stenosis are achievable or satisfactory therapeutic results (decreased USMC hyperplasin as compound insulin controls) are achievable, usually within the range of the expected effective dose range, i.e., 10.0 ng to 1.0 mg.
  • the Relaxin composition is to be administered to the warm-blooded animals so that the composition remains resident in the vessel wall for about 24 to 48 hours, although shorter and longer residence periods may be acceptable.
  • the Relaxin compound(s) of the present invention or derivatives thereof, prepared and used as described herein, provide means of jLn vivo therapeutic treatment for areas of vascular stenosis.

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  • Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
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  • Gastroenterology & Hepatology (AREA)
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Abstract

Compositions et procédés d'utilisation desdites compositions adaptées pour être administrées à un animal à sang chaud, lesquelles comportent un polypeptide ou un dérivé dudit polypeptide pouvant être administré à un animal en vue de produire une souplesse cellulaire fiable et un remodelage de la matrice extracellulaire dans des régions d'obstruction de vaisseaux, ce qui permet un traitement thérapeutique entraînant une réduction des dommages subis par les cellules des muscles lisses.
PCT/US1994/010381 1993-09-14 1994-09-14 Traitement therapeutique destine a inhiber l'obstruction des vaisseaux sanguins a l'aide d'un polypeptide WO1995007711A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP94927421A EP0722334A1 (fr) 1993-09-14 1994-09-14 Traitement therapeutique destine a inhiber l'obstruction des vaisseaux sanguins a l'aide d'un polypeptide
JP7509330A JPH09502726A (ja) 1993-09-14 1994-09-14 血管障害を防ぐポリペプチドを用いる治療的処置
AU76871/94A AU7687194A (en) 1993-09-14 1994-09-14 Therapeutic treatment for inhibiting blood vessel blockage using a polypeptide

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US12098093A 1993-09-14 1993-09-14
US08/120,980 1993-09-14

Publications (1)

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WO1995007711A1 true WO1995007711A1 (fr) 1995-03-23

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PCT/US1994/010381 WO1995007711A1 (fr) 1993-09-14 1994-09-14 Traitement therapeutique destine a inhiber l'obstruction des vaisseaux sanguins a l'aide d'un polypeptide

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JP (1) JPH09502726A (fr)
AU (1) AU7687194A (fr)
WO (1) WO1995007711A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1326627A1 (fr) * 2000-10-04 2003-07-16 Molecular Medicine Research Institute Methodes de modulation de l'apoptose par l'administration d'agonistes ou d'antagonistes de relaxine
US6723702B2 (en) 2000-02-09 2004-04-20 Ras Medical, Inc. Use of relaxin treat diseases related to vasoconstriction
US7833526B2 (en) 2000-10-04 2010-11-16 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US7878978B2 (en) 2004-03-18 2011-02-01 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Use of relaxin to increase arterial compliance

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5145962A (en) * 1982-08-12 1992-09-08 Howard Florey Institute Of Experimental Physiology And Medicine Human pro relaxin polypeptides

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5145962A (en) * 1982-08-12 1992-09-08 Howard Florey Institute Of Experimental Physiology And Medicine Human pro relaxin polypeptides

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6723702B2 (en) 2000-02-09 2004-04-20 Ras Medical, Inc. Use of relaxin treat diseases related to vasoconstriction
EP1326627A1 (fr) * 2000-10-04 2003-07-16 Molecular Medicine Research Institute Methodes de modulation de l'apoptose par l'administration d'agonistes ou d'antagonistes de relaxine
EP1326627A4 (fr) * 2000-10-04 2004-06-16 Molecular Medicine Res Inst Methodes de modulation de l'apoptose par l'administration d'agonistes ou d'antagonistes de relaxine
US7833526B2 (en) 2000-10-04 2010-11-16 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US8119136B2 (en) 2000-10-04 2012-02-21 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US9534034B2 (en) 2000-10-04 2017-01-03 Molecular Medicine Research Institute Methods of modulating apoptosis by administration of relaxin agonists or antagonists
US7878978B2 (en) 2004-03-18 2011-02-01 University Of Pittsburgh- Of The Commonwealth System Of Higher Education Use of relaxin to increase arterial compliance
US8602998B2 (en) 2004-03-18 2013-12-10 University of Pittsburgh—of the Commonwealth System of Higher Education Use of relaxin to increase arterial compliance

Also Published As

Publication number Publication date
EP0722334A1 (fr) 1996-07-24
AU7687194A (en) 1995-04-03
JPH09502726A (ja) 1997-03-18

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