[go: up one dir, main page]

WO2005016333A1 - Utilisation de tyrphostines pour traiter une resténose - Google Patents

Utilisation de tyrphostines pour traiter une resténose Download PDF

Info

Publication number
WO2005016333A1
WO2005016333A1 PCT/CA2004/001487 CA2004001487W WO2005016333A1 WO 2005016333 A1 WO2005016333 A1 WO 2005016333A1 CA 2004001487 W CA2004001487 W CA 2004001487W WO 2005016333 A1 WO2005016333 A1 WO 2005016333A1
Authority
WO
WIPO (PCT)
Prior art keywords
receptor
igf
angll
kinase
phosphorylation
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/CA2004/001487
Other languages
English (en)
Inventor
Peter Zahradka
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
ST BONIFACE GENERAL HOSPITAL
Original Assignee
ST BONIFACE GENERAL HOSPITAL
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 ST BONIFACE GENERAL HOSPITAL filed Critical ST BONIFACE GENERAL HOSPITAL
Publication of WO2005016333A1 publication Critical patent/WO2005016333A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/432—Inhibitors, antagonists
    • A61L2300/434—Inhibitors, antagonists of enzymes

Definitions

  • the present invention relates generally to the field of pharmaceutical compositions and medical treatments. More specifically, the present invention relates to pharmaceutical compositions for treating restenosis and methods of using same.
  • Angiotensin II (Angll) is a peptide hormone that promotes the growth and proliferation of vascular smooth muscle cells (SMCs). Although Angll associates with high affinity to two distinct G protein-coupled receptors, ATi and AT 2 , the mitogenic actions of Angll are primarily exerted through the AT-i receptor (Touyz and Schiffrin, 2000, Pharmacol Rev 52: 639-672).
  • PI3-kinase phosphatidylinositol 3-kinase
  • IGF-1 receptor transactivation is essential for the activation of specific signal transduction pathways by Angll. Restenosis is caused by vascular stress or injury and leads to vessel wall thickening and loss of blood flow. These stresses may be, for example, mechanical, hypoxia, injury, shear-stress, pharmacological, infectious, inflammatory, oxidative, immunogenic, diabetic or pressure.
  • the normal arterial vessel wall consists of a regular arrangement of endothelial, smooth muscle and fibroblast cells, present in three distinct layers of endothelium, media and adventitia. A single layer of endothelial cells forms the luminal barrier to blood-borne signals that modulate vascular function.
  • the adventitia which forms the outer layer around the artery, consists primarily of extracellular matrix as well as some fibroblasts, nerve fibres and microvessels.
  • the media consists of numerous layers of smooth muscle cells (SMCs) intermixed with extracellular matrix that is bound by the internal and external elastic lamina.
  • SMCs smooth muscle cells
  • the response to injury or other stress stimuli varies between the different cellular components of the vessel. Endothelial cells are capable of proliferation and migration, properties that permit re-endothelialization of the vessel after denudation or injury (Reidy, 1985, Lab Invest 53: 513-520).
  • Medial SMCs are also able to reversibly modulate their phenotype which allows for their proliferation and/or migration into the intima at the site of injury (Schwartz et al, 1995, Circ Res 77: 445-465). It is these characteristics that lead to the adaptive and pathogenic growth of SMCs which is key to vascular remodelling and lesion formation. This is of particular concern for the treatment of coronary disease, wherein a common treatment for constricted, clogged or narrowed coronary arteries is balloon angioplasty. Angioplasty involves the use of a balloon-tipped catheter which is inserted into the heart's vessels to open partially blocked, or stenotic, coronary arteries.
  • restenosis While balloon angioplasty does widen the restricted artery, a significant number of patients have renewed narrowing of the widened segment soon after the procedure. This subsequent narrowing of the artery is called restenosis and can necessitate the repetition of the angioplasty procedure or require alternative treatment such as coronary bypass graft surgery. Furthermore, restenosis occurs as a result of trauma to the vessel regardless of the method by which the injury is inflicted. Therefore, restenosis is not exclusive to angioplasty and is a common result of other (cardiac or peripheral) revascularization procedures (eg. stenting) or procedures involving vascular grafting (eg. bypass surgery, organ transplantation). It is also a problem associated with hemoaccess and other procedures involving long term intravenous delivery.
  • Restenosis appears to be a response to injury of arterial wall, and appears to consist of the following events: platelet adhesion and aggregation on the damaged endothelium; release of platelet-derived growth factors; inflammation of the injured zone (Kornowski et al, 1998, J Am Coll Cardiaol 31: 224-230); secretion of specification chemotactic proteins from the damaged cells leading to recruitment of monocytes to the site of injury (Furukawa et al, 1999, Circ Res 84: 306-314); differentiation of monocytes into macrophages that produce matrix metalloproteinases required for cell migration; dedifferentiation of the smooth muscle cells after their activation by the growth factors; migration and proliferation of transformed smooth muscle cells, with secretion of extracellular matrix material; and re-growth of endothelium over the injured area.
  • PCT Application WO 93/23067 teaches the use of fragments of IGF-1 as antagonists for treating cell proliferative disorders such as cancer, restenosis and asthma.
  • US Patent 6,368,826 describes an IGF-1 receptor binding protein (IIP-10) and its use in treating cancers, diabetes, neurodegenerative disorders and bone diseases.
  • US Patent 6,518,238 teaches the use of IGF or IGF complexed with IGFBP-3 for treating psychological and/or metabolic disorders.
  • PCT WO01/72771 teaches the use of short peptides having IGF-1 binding domains as IGF-1 receptor agonists and antagonists.
  • PCT WO02/102805 teaches the use of cyclolignans as IGF-1 auto-phosphorylation decoy substrates.
  • the cyclolignans are not structurally related to AG1024 or AG538.
  • US Patent 5,789,427, US Patent 5,763,441 , US Patent 5,773,476, US Patent 5,849,742, US Patent 5,712,395, US Patent 6,358,954, US Patent 5,914,343 and PCT Application WO 99/67636 identify AG 1024 as "M14" and describe compounds structurally similar to AG538 (see Fig 2c) but containing an additional amide bond.
  • these patents teach the use of these compounds for treating cell proliferative disorders, primarily cancers (US Patent 5,773,476) as well as vasculogenesis and angiogenesis of tumors (US Patent 5,763,441) which are distinctly different diseases from restenosis.
  • a method of treating or preventing restenosis comprising: administering an effective amount of a pharmaceutical composition having an active ingredient selected from the group consisting of AG538, AG1024 or a mixture thereof to an individual in need of such treatment.
  • a pharmaceutical composition for treating restenosis said pharmaceutical composition having as an active ingredient AG538, AG1024 or a combination thereof.
  • a medical device coated with an effective amount of a pharmaceutical composition having as an active ingredient AG538, AG1024 or a combination thereof there is provided.
  • a method of manufacturing a pharmaceutical composition comprising: combining an effective amount of AG538, AG1024 or a mixture thereof with a suitable carrier.
  • Angiotensin II stimulates tyrosine phosphorylation of the IGF-1 receptor.
  • Panel A Quiescent SMCs were stimulated with Angll (1 ⁇ M) and the cells lysed at the indicated time points. IGF-1 receptor phosphorylation was monitored by Western blotting with phosphorylation-specific antibody (dilution 1 :1000).
  • Panel B Intensities of , phosphorylated IGF-1 receptor bands from three independent experiments were quantified by scanning densitometry and normalized to control bands for each experiment. Values were subsequently averaged and plotted as means ⁇ SEM.
  • Panel C SMCs treated with and without 1 ⁇ M Angll for 10 min were lysed with RIPA buffer and phosphorylated IGF-1 and insulin receptors immunoprecipitated with phospho-specific antibody. Two immunoprecipitations were performed for each sample and the recovered protein was blotted onto the same membrane.
  • FIG. 3 AG1024 and AG538 are specific inhibitors of the IGF-1 receptor kinase and block activation by Angll.
  • Quiescent SMCs were pretreated for 15 min with various receptor tyrosine kinase inhibitors as indicated, and each inhibitor was used at a concentration of 5 ⁇ M.
  • Phosphorylation of the IGF-1 receptor was monitored in samples stimulated with 0.1 ⁇ M IGF-1 (panel A) while phosphorylation of p70 S6K was used to assess activation with 1 ⁇ g/mL EGF (panel B).
  • Figure 4 Angll-dependent activation of PI3-kinase and its downstream effectors is blocked by inhibitors of the IGF-1 receptor kinase.
  • Panel A Quiescent SMCs were stimulated with 1 ⁇ M Angll for 10 min, then lysed. Inhibitors (5 ⁇ M) were added 15 min prior to Angll. Tyrosine phosphorylation of the PI3-kinase p85 subunit was determined by Western blot analysis after immunoprecipitation.
  • Panel B Activation of PDK1 and p70S6K was measured by Western blot analysis with phosphorylation-specific antibodies (diluted 1:1000) after treatment with 1 ⁇ M Angll or 0.1 ⁇ M IGF-1 in the presence of 5 ⁇ M inhibitors.
  • Figure 5 AG1024 does not inhibit MAP kinase activation by Angll.
  • Phospho- specific antibodies were employed to monitored MAP kinase activation in response to 10 min incubation with 1 ⁇ M Angll or 0.1 ⁇ M IGF-1. Inhibitors added 15 min prior to stimulation were used at a concentration of 5 ⁇ M.
  • Panel A Samples were analyzed by Western blotting, with antibodies were diluted 1 :1000.
  • Panel B Immunostaining for phosphorylated MAP kinase (antibody diluted 1 :100) is shown for control quiescent cells (A), as well as cells stimulated with Angll (B), Angll plus AG1024 (C) or IGF-1 (D). Treatment conditions were identical to those described for panel A.
  • Figure 6 Signalling pathways activated by Angll and mediated by IGF-1 receptor transactivation.
  • Figure 7 Graph showing the concentration effect of AG1024 on neointimal formation. DESCRIPTION OF THE PREFERRED EMBODIMENTS Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs.
  • vascular stenosis refers to vessel wall thickening, clogging or constriction and loss of blood flow.
  • the stresses leading to stenosis may be, for example, mechanical, hypoxia, injury, shear-stress, pharmacological, infectious, inflammatory, oxidative, immunogenic, diabetic or pressure.
  • angioplasty refers to procedures and methods involved in the opening or unclogging of blocked arteries.
  • angioplasty involves the use of a balloon-tipped catheter which is inserted into the heart's vessels to open partially blocked, or stenotic, coronary arteries. While balloon angioplasty does widen the restricted artery, a significant number of patients have renewed narrowing of the widened segment soon after the procedure. This subsequent narrowing of the artery is called restenosis and can necessitate the repetition of the angioplasty procedure or require alternative treatment such as coronary bypass graft surgery.
  • Teyrphostins refers to a family of tyrosine kinase inhibitors.
  • AG1024 refers to 3-bromo-5-t-butvl-4-hvdroxv-benzylidenemalonjMI-e.
  • AG538 refers to -alpha;c ang,-(3,4-dihydroxy) cinnamoyl-(3',4'-dihydroxyphenyJl_ ketone.
  • the term "treating" in its various grammatical forms refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a disease state, disease progression, disease causitive agent other abnormal condition.
  • Described herein is a method of treating or preventing restenosis comprising administering to an individual in need of such treatment an effective amount of AG1024 and/or AG538.
  • a pharmaceutical composition comprising as the active ingredient AG1024 and/or AG538 as well as medical devices coated or impregnated with said pharmaceutical composition.
  • Angiotensin II (Angll) activates phosphatidylinositol 3-kinase (PI3-kinase), a known effector of receptor tyrosine kinases.
  • SMCs smooth muscle cells
  • Angll smooth muscle cells
  • IGF-1 receptor phosphorylation was maximally stimulated within 10 minutes by Angll. Inclusion of an IGF-1 neutralizing antibody in the culture media did not prevent IGF-1 receptor phosphorylation following Angll treatment, which argues that a paracrine/autocrine loop is not required. Furthermore, this process was blocked by losartan and PP-1, indicating stimulation of IGF-1 receptor phosphorylation occurs via AT ! receptor-dependent activation of Src kinase. The functional significance of IGF-1 receptor transactivation was examined with selective inhibitors of the IGF-1 receptor kinase (AG1024, AG538).
  • Angiotensin II is a critical element in the vascular response to injury, operating primarily to promote conversion of smooth muscle cells (SMCs) to a phenotypic state which permits migration and proliferation (Hayashy et al, 1998, JBC 273: 28860- 28867).
  • SMCs smooth muscle cells
  • Angll stimulates tyrosine phosphorylation of key protein mediators of intracellular signalling pathways associated with migration and proliferation (Yin et al, 2003, Int J Biochem Cell ⁇ /o/ 35: 780-783).
  • mechanistic information detailing how G-protein-coupled Angll receptors stimulate tyrosine phosphorylation is limited.
  • IGF-1 receptor kinase As an intermediate for the transduction of signals originating from Angll receptors.
  • Our rationale for examining the IGF-1 receptor was based on published evidence that showed both the IGF-1 receptor and IRS-1 are tyrosine phosphorylated in response to Angll (Du et al, 1996; Ali et al, 1997).
  • phosphorylation of the IGF-1 receptor was shown to be ATi receptor- dependent and mediated by Src kinase.
  • IGF-1 receptor transactivation has a critical role in the cellular actions of Angll.
  • Receptor transactivation is a relatively recent concept, originating from evidence that phosphorylation of receptor tyrosine kinases occurs in response to agonists of G protein-coupled receptors (Luttrell, 2002, Can J Physiol Pharmacol 80: 375-382; Daub et al, 1996, Nature 379: 557-560; Marinissen and Gutkind, 2001 , Trends Pharmacol Sci 22: 368-376).
  • SMCs treated with Angll tyrosine phosphorylation of the EGF, PDGF and IGF-1 receptors has been observed [reviewed in Saito and Berk, 2001 , J Mol Cell Cardiol 33: 3-7; Eguchi and Inagami, 2000, Regul Pept 91: 13-20].
  • EGF receptor phosphorylation has been independently confirmed and shown to mediate, for example, ERK1/2 phosphorylation, c-fos expression and protein synthesis (Voisin et al, 2002; Eguchi et al, 1998; Eguchi et al, 1999, JBC 274: 36843- 36851). The mechanism which mediates EGF receptor activation, however, has yet to be clarified.
  • the ability to inhibit cell proliferation with a neutralizing antibody cannot be equated with the lack of an effect on receptor transactivation, which we assayed directly in this study. Rather, transactivation of the IGF-1 receptor by the AT ! receptor occurs in the absence of IGF-1 secretion, while progression through G1 phase requires IGF-1 synthesis and secretion prior to IGF-1 receptor activation. The latter view is supported by evidence showing Angll also stimulates both IGF-1 and IGF-1 receptor gene expression (Brink et al, 1999, Hypertension 34: 1053-1059).
  • the ATi receptor is a member of the G protein-coupled receptor family which operates through specific heterotrimeric G proteins.
  • Src kinase has been identified as the leading candidate for mediating receptor tyrosine kinase transactivation in response to Angll (Eguchi et al, 1998; Bokemeyer et al, 2000, Kidney Int 58: 549-558; Luttrell et al, 1997, JBC 272: 4637-4644), and we have similarly shown Src kinase is required for IGF-1 receptor transactivation.
  • IGF-1 receptor phosphorylation is required for the activation of PI3-kinase by Angll.
  • Velloso et al (Velloso et al, 1996) previously showed that PI3-kinase associates with phosphorylated IRS-1 and IRS-2 following Angll stimulation of heart tissue, and Angll also triggers phosphorylation of IRS-1 in SMCs (Ali et al, 1997).
  • AG1024 inhibition with AG1024 established that PI3-kinase was downstream of the IGF-1 receptor.
  • experiments with AG1024 and LY294002 indicated that p70 S6K and PDK-1 also followed PI3-kinase.
  • Src kinase can be viewed as controlling two distinct pathways leading from the ATi receptor ( Figure 6).
  • Src kinase controls MAP kinase activity and nuclear translocation. This process is necessary for immediate early gene expression.
  • tyrosine kinase-independent activation of MAP kinase by the IGF-1 receptor could also explain why this event is both Src kinase-dependent and AG1024-insensitive (Yau et al, 1999, Eur J Biochem 266: 1147-1157).
  • Src kinase mediates IGF-1 receptor transactivation, which is required for PI3-kinase activation.
  • the IGF-1 receptor likely functions as a scaffold for p85 binding, and synthesis of PI3-P results in PDK-,1 activation, p70 S6K phosphorylation and increased protein synthesis. How does this scheme reconcile our evidence that MAP kinase phosphorylation is blocked by inhibition of PI3-kinase (Yau et al, 2003, Eur J Biochem 270: 101-110)? It is becoming obvious that each PI3-kinase isoform has a distinct function in the transduction of signals within cells.
  • the p110 isoform of PI3-kinase (Class l B ) may be particularly relevant to Angll stimulation, since its activation is mediated by G P ⁇ subunits (Vanhaesebroeck and Waterfield, 1999). A role for both PI3-kinase isoforms in the transduction of signals from the AT ! receptor may therefore be projected. Appreciating these distinctions may also help alleviate the confusion surrounding the roles of individual PI3-kinase isoforms in signalling by G protein-coupled receptors. As can be seen in Figure 7, AG1024 is effective at dosages of 10 "6 M to 10 "9 M.
  • AG1024 and/or AG538 is arranged to be delivered at a local concentration of between 10 "6 M to 10 "9 M. In yet other embodiments, AG1024 and/or AG538 may be delivered at a local concentration of between 10 "6 M to 10 " 9 M.
  • AG1024 and/or AG538 is combined with an adhesive agent in a pharmaceutical composition that can be applied locally. In some embodiments, AG1024, AG538 or combinations thereof in a therapeutically effective amount may be combined with a pharmaceutically or pharmacologically acceptable carrier, excipient or diluent, either biodegradable or non- biodegradable.
  • Exemplary examples of carriers include, but are by no means limited to, for example, poly(ethylene-vinyl acetate), copolymers of lactic acid and glycolic acid, poly(lactic acid), gelatin, collagen matrices, polysaccharides, poly(D,L lactide), poly(malic acid), poly(caprolactone), celluloses, albumin, starch, casein, dextran, polyesters, ethanol, mathacrylate, polyurethane, polyethylene, vinyl polymers, glycols, mixtures thereof and the like.
  • Standard excipients include gelatin, casein, lecithin, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glyceryl monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycols, polyoxyethylene stearates, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose,.
  • the carrier may be pH-sensitive, thermo-sensitive, thermo-gelling, arranged for sustained release or a quick burst.
  • carriers of different classes may be used in combination for multiple effects, for example, a quick burst followed by sustained release.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof is combined with an adhesive agent.
  • the pharmaceutical composition can be localized to the intended area, for example, a damaged vessel, thereby limiting side effects.
  • the combination has suitable release kinetics so that delivery of the active agent occurs over an extended period of time which may be necessary to ensure efficacy.
  • the adhesive agent is non-toxic.
  • AG1024 and/or AG538 is suspended in a non- toxic, biodegradable fibrin glue (Grecto et al, 1991 , J Biomed Mater Res 25:39-51 ; Zilch and Lambiris, 1986, Arch Orthop Trauma Surg 106:36-41), which consists of separate fibrinogen and thrombin components purified from human or bovine plasma (Senderoff et. al, 1991 , J Parenteral Sci Technol 45:2-6; Katz and Spera, 1998, Medical Device and Diagnostic Industry Magazine, April).
  • a fibrin glue is TisseelTM (Immuno AG, Vienna, Austria).
  • Tisseel adhesive biomaterials are being manufactured by Thermogenesis (Rancho Cordova, CA), Fusion Medical Technologies, Inc. (Mountain View, CA), and CryoLife, Inc. (Kennesaw, GA), which offers photoactivated fibrin sealants.
  • V.I. Technologies (New York City) is developing a fibrin sealant similar to Tisseel, as are Haemacure Corp. (Sarasota, FL), Convatec/Bristol-Myers Squibb (Skillman, NJ), and BioSurgical Corp. (Pleasanton, CA).
  • fibrin glues have been successfully used to deliver growth factors to promote angiogenesis (Fasol et al, 1994, Thorac Cardiovasc Surg 107: 1432-1439) or inhibit intimal hyperplasia (Zarge et al, 1997, J Vase Surg 25: 840-848), and to deliver antibiotics in vitro (Greco et al, 1991 , J Biomed Mater Res 25: 39-51).
  • This approach allows for the delivery of pharmacologically potent concentrations locally, without any significant release of the drug systemically.
  • other suitable biocompatible or biodegradable adhesives known in the art may also be used.
  • AG1024 and/or AG538 are arranged to be delivered at a local concentration when used in this combination. It is important to note that a therapeutic dosage of AG1024 and/or AG538 will of course depend on at least the age, weight and condition of the patient as well as the location of treatment, where appropriate.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof may be contained within or adapted to be released by a surgical or medical device, for example, stents, catheters, prostheses, sutures and the like.
  • pharmaceutical composition comprising AG1024, AG538 or a combination thereof at concentrations or dosages described above may be incorporated into nylon microcapsules and applied to the surface of the stent or device.
  • the device may be coated with a film composed of, for example, cellulose, hyaluronic acid, chitosan, ethylene vinyl acetate, or poly lactic acid, impregnated with the pharmaceutical composition comprising as an active ingredient a therapeutic amount of AG1024, AG538 or a combination thereof.
  • the device may be coated with a thermo-sensitive gel such that the pharmaceutical composition comprising AG1024, AG538 or a combination thereof is released when the device is implanted.
  • stents are used to expand the lumen of a body passageway. This involves inserting the stent into the passageway such that the passageway is expanded.
  • a preinsertion examination for example, either a diagnostic imaging procedure or direct visualization at the time of surgery is performed to determine the appropriate location for stent insertion.
  • a guide wire is advanced through the proposed site of insertion.
  • a delivery catheter is then passed over the guide wire, allowing insertion of the catheter into the desired position.
  • the stent is then expanded by means known in the art.
  • the stent may be coated for example by spraying or dipping the stent with or in the pharmaceutical composition comprising AG1024, AG538 or a combination thereof described above, or the stent may be coated with an absorption-promoting substance, such as hydrogel, first.
  • the stent may be surrounded in a sleeve, mesh or other structure impregnated with the pharmaceutical composition comprising AG1024, AG538 or a combination thereof and arranged to release the pharmaceutical composition comprising a therapeutic amount of AG1024, AG538 or a combination thereof over time.
  • a pharmaceutical composition comprising AG1024, AG538 or a combination thereof at concentrations or dosages described above may be encapsulated for delivery.
  • AG1024 and/or AG538 may be encapsulated in biodegradable microspheres, microcapsules, microparticles, or nanospheres.
  • the delivery vehicles may be composed of, for example, hyaluronic acid, polyethylene glycol, poly(lactic acid), gelatin, poly(E-caprolactone), or a poly(lactic-glycolic) acid polymer. Combinations may also be used, as, for example, gelatin nanospheres may be coated with a polymer of poly(lactic-glycolic) acid. As will be apparent to one knowledgeable in the art, these and other suitable delivery vehicles may be prepared according to protocols known in the art and utilized for delivery of the pharmaceutical composition comprising AG1024, AG538 or a combination thereof. In some embodiments, the delivery vehicle may be coated with an adhesive for localizing the pharmaceutical composition comprising AG1024, AG538 or a combination thereof to the area of interest.
  • the delivery vehicle may be suspended in saline and used as a nanospray for aerosol dispersion onto an area of interest. Furthermore, the delivery vehicle may be dispersed in a gel or paste, thereby forming a nanopaste for coating a tissue or tissue portion.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof as described above may be combined with permeation enhancers known in the art for improving delivery. Examples of permeation enhancers include, but are by no means limited to those compounds described in U.S. Pat. Nos.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof in any suitable form as described above may be combined with biological or synthetic targetting molecules, for example, site-specific binding proteins, antibodies, lectins or ligands, for targetting the pharmaceutical composition comprising AG1024, AG538 or a combination thereof to a specific region or location.
  • biological or synthetic targetting molecules for example, site-specific binding proteins, antibodies, lectins or ligands, for targetting the pharmaceutical composition comprising AG1024, AG538 or a combination thereof to a specific region or location.
  • Angll is a critical element in the vascular response to injury, as Angll promotes conversion of SMCs to a phenotypic state which permits migration and proliferation by phosphorylating a number of tyrosine kinase receptors, including PI3-kinase.
  • AG1024 and AG538 prevent at least phosphorylation of PI3-kinase, these compounds constitute an effective treatment for restenosis, as described herein.
  • pharmaceutical composition comprising a therapeutically effective amount of AG1024, AG538 or a combination thereof should be able to restrict progression of this condition, that is, reduce the incidence and/or severity of the lesions.
  • the incidence or severity of symptoms associated with all vascular procedures involving grafting, puncturing or producing intimal damage can be reduced by the above-described compounds, as could inflammation and/or irritation accompanying valve replacements, catheters, prosthesis, implanted devices, pacemakers, nerve stimulators, patches, organ transplants, small vessel vaeulopathy, wound repair, or psoriasis.
  • the symptoms associated with any inflammation or inflammatory disease that is localized to a defined region can be ameliorated using the pharmaceutical composition' comprising a therapeutically effective amount of AG1024, AG538 or a combination thereof described above.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof may be localized through the use of an adhesive, impregnated mesh or targetting molecule as described herein, or the device or organ may be coated or infused with the pharmaceutical composition comprising AG1024, AG538 or a combination thereof as described herein.
  • the pharmaceutical composition comprising AG1024, AG538 or a combination thereof could also be sprayed or applied to tissue grafts or organs prior to transplantation. Specifically, graft rejection is characterized by lesion formation, inflammation and necrosis.
  • the pharmaceutical composition comprising a therapeutically effective amount of AG1024, AG538 or a combination thereof will accomplish at least one of the following: prolong the life of the graft; decrease the side effects associated with immunosuppressive therapy and decrease accelerated atherosclerosis associated with transplants.
  • a mesh coated or arranged to release the pharmaceutical composition comprising AG1024, AG538 or a combination thereof may be used in lieu of spray application.
  • the sprays or meshes could also be used to treat, for example, venous leg ulcers, skin grafts, post-operative hypertrophy, hyperplasia, hypertrophic burn scars, hypertrophic gastropathy, cardiac hypertrophy associated with congestive heart failure and hypertrophic cardiopathy, or hypertension.
  • hypertension is an increase in smooth muscle cell volume within a blood vessel due to excessive pressure, lack of oxygen/nutrients or enhanced production of hypertrophy-inducing factors released as a result of trauma distinct from the site of action (for example, kidney disease).
  • hypertrophic cardiac disease for example, congestive heart failure, hypertrophic cardiomyopathy, valve replacement surgery
  • Cellular hypertrophy and inflammation occur in the region affected by the causative factor.
  • these disorders also require cell migration and differentiation, meaning that the pharmaceutical composition comprising AG1024, AG538 or a combination thereof may alleviate some of the associated symptoms.
  • SMCs porcine coronary artery smooth muscle cells
  • SMCs were grown to 70% confluence in D- MEM containing 20% FBS, 2 mM glutamine, 50 ⁇ g/mL streptomycin, 50 ⁇ g/mL penicillin, and subsequently incubated in serum-free D-MEM supplemented with 11 ⁇ g/mL pyruvate, 5 ⁇ g/mL transferrin, 10 "9 M selenium, 2X10 "4 M ascorbate and 10 "8 M insulin for 5 days. Cells were used only after the second passage to maintain consistency between cultures.
  • Antibodies employed during the course of this investigation were obtained from either Cell Signaling (phospho-p44/42 MAP kinase (thr202/tyr204), phospho-p70 S6K (thr389), phospho-PDK1 (ser241), phospho-insulin (tyr1146)/IGF-1 (tyr1131) receptor, PY100), Upstate Biotechnology (PI3-kinase p85 subunit) or Santa Cruz Biotechnology (IGF-1 receptor ⁇ -subunit, insulin receptor ⁇ -subunit).
  • Cell lysates were prepared from 100-mm culture dishes by addition of either 1.0 mL lysis buffer (1% NP-40, 20 mM Tris-HCI (pH 7.5), 10% glycerol, 137 mM NaCI, 1 mM MgCI 2 , 1 mM PMSF, 0.4 mM orthovanadate, 1 mM NaF) or RIPA buffer (150 mM NaCI, 1% NP-40, 0.25% sodium deoxycholate, 0.1% SDS, 50 mM Tris-HCI (pH 8.0), 1 mM EGTA, 1 mM EDTA).
  • lysis buffer 1% NP-40, 20 mM Tris-HCI (pH 7.5), 10% glycerol, 137 mM NaCI, 1 mM MgCI 2 , 1 mM PMSF, 0.4 mM orthovanadate, 1 mM NaF
  • RIPA buffer 150 mM NaCI, 1% NP-40, 0.25% sodium
  • the plates were scraped and the lysates cleared by centrifugation (10 min, 12,000 ⁇ g at 4°C). Protein concentrations were measured and aliquots of 100 ⁇ g protein were mixed for 2 h at 4°C with Protein G Sepharose (Amersham Pharmacia). Protein G Sepharose was subsequently removed by centrifugation at 12,000*g for 5 min at 4DC. Each aliquot was then mixed over 2.5 - 4 h at 4 ⁇ C with 4 ⁇ g of antibody. Protein G Sepharose was added for an additional 0.5 - 2 h. The Protein G Sepharose beads were subsequently collected by centrifugation (12,000*g for 5 min at 4°C) and washed 4 times with 1.0 mL lysis buffer.
  • FIG. 2D Similar results ( Figure 2D) were obtained with a neutralizing IGF-1 receptor antibody (Ab-1 , clone IR-3, Oncogene), which blocks binding of IGF-1 to the receptor (Rohlik et al, 1987, Biochem Biophys Res Commun 149: 276- 281).
  • the IGF-1 receptor tyrosine kinase can be selectively inhibited: Although inhibitors of tyrosine kinases are commercially available, few of these compounds have shown selectivity for either the insulin or IGF-1 receptors. We therefore tested several compounds that have been reported to inhibit the IGF-1 receptor kinase, and compared their actions with those of other receptor tyrosine kinase inhibitors.
  • the panel of inhibitors included a PDGF receptor inhibitor (AG1295), an EGF receptor inhibitor (AG1478) and two putative IGF-1 receptor inhibitors (AG538, AG1024) (Kovalenko et al, 1994, Cancer Res 54: 6106-6114; Levitzki and Gazit, 1995, Science 267: 1782-1788; Blum et al, 2000, Biochemistry 39: 15705-15712; Parrizas et al, 1997, Endocrinology 138: 1427-1433).
  • Quiescent SMCs were stimulated with IGF-1 (0.1 ⁇ M), which resulted in an increase in IGF-1 receptor phosphorylation relative to control (Figure 3A).
  • HNMPA-(AM) 3 hydroxy-2-naphthalenylmethylphosphonic acid tris-acetoxymethyl ester, (Saperstein et al, 1989, Biochemistry 28: 5694-5701) was also tested in these experiments. This compound consistently killed the cells when concentrations capable of preventing receptor phosphorylation (>100 ⁇ M) were employed, even with only a 15 minute pre-incubation (data not shown). HNMPA-(AM) 3 was therefore not used.
  • IGF-1 receptor kinase inhibitors prevent PI3-kinase activation: ATi receptor stimulation by Angll increases PI3-kinase activity in SMCs (Saward and Zahradka, 1997). Concurrent with this change in activity, the p85 regulatory subunit undergoes tyrosine phosphorylation (Saward and Zahradka, 1997). To determine whether p85 phosphorylation was IGF-1 receptor-dependent, quiescent SMCs were stimulated with Angll in the presence and absence of AG1024. Cells were lysed after 10 min, and p85 was immunoprecipitated.
  • PI3-kinase controls this process through the sequential activation of PDK-1 and p70 S6K (Vanhaesebroeck et al, 2001 , Annu Rev Biochem 70: 535-602). We therefore monitored PDK-1 and p70 S6K to determine whether their phosphorylation was inhibited with AG1024. As expected, the phosphorylation of PDK-1 and p70 S6K was increased in response to Angll and inhibited by LY294002, a selective inhibitor of PI3-kinase ( Figure 4B). Like LY294002, AG1024 also prevented PDK-1 and p70 S6K phosphorylation ( Figure 4B).
  • IGF-1 receptor transactivation regulates specific signalling pathways downstream of PI3-kinase.
  • ATi receptor-dependent stimulation of MAP kinase is IGF-1 receptor independent:
  • PI3-kinase activation mediates stimulation of the MAP kinase cascade in response to Angll (Yau et al, 2003).
  • Activation of Erk1/2 MAP kinase by PI3-kinase apparently involves a cascade that is distinct from the PDK-1 and p70 S6K -dependent pathway that leads to protein synthesis (Vanhaesebroeck et al, 2001).
  • AG1024 did not affect the stimulation produced with Angll treatment (panel C). These data indicate that IGF-1 receptor transactivation . is essential for PI3-kinase activation in response to Angll, but is apparently not required for MAP kinase phosphorylation. AG1024 is capable of preventing neointimal formation in an organ culture model of restenosis. Porcine hearts were obtained from the local abattoir, transported to the laboratory on ice, and the left descending coronary artery carefully exposed. The coronary arteries were injured in situ by inflation of an angioplasty catheter (3.5 mm x 20 mm), then carefully dissected free of the underlying heart tissue.
  • an angioplasty catheter 3.5 mm x 20 mm
  • Each injured or non-injured control vessel was divided into 4 segments of 5 mm and individual segments were placed into 24- well dishes with 1.0 ml growth medium (Dulbecco's modified Eagle medium containing 20% fetal bovine serum) plus various concentrations of AG1024.
  • the vessel segments were incubated in a standard C02 incubator for 14 days, with medium plus treatments refreshed every second day.
  • Neointimal formation was quantified by morphometric analysis of each vessel segment. Briefly, the segments were frozen in O.C.T. medium after removal of 1.5 mm from each end. Sections of 7 ⁇ m obtained with a cryostat were stained with Lee's methylene blue.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Surgery (AREA)
  • Vascular Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé permettant de traiter ou de prévenir une resténose. Ce procédé consiste à administrer une composition pharmaceutique comprenant les inhibiteurs AG538 et/ou AG1024 à un individu nécessitant un tel traitement. Cette invention se rapporte également à des compositions pharmaceutiques servant à traiter une resténose et contenant les inhibiteurs AG538 et/ou AG1024, ainsi qu'à des dispositifs médicaux revêtus ou imprégnés desdits inhibiteurs AG538 et/ou AG1024.
PCT/CA2004/001487 2003-08-14 2004-08-16 Utilisation de tyrphostines pour traiter une resténose Ceased WO2005016333A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US49478703P 2003-08-14 2003-08-14
US60/494,787 2003-08-14
US53652904P 2004-01-15 2004-01-15
US60/536,529 2004-01-15

Publications (1)

Publication Number Publication Date
WO2005016333A1 true WO2005016333A1 (fr) 2005-02-24

Family

ID=34198007

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CA2004/001487 Ceased WO2005016333A1 (fr) 2003-08-14 2004-08-16 Utilisation de tyrphostines pour traiter une resténose

Country Status (1)

Country Link
WO (1) WO2005016333A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006087718A1 (fr) * 2005-02-17 2006-08-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Prolongement de duree de vie avec des medicaments

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995002420A2 (fr) * 1993-07-15 1995-01-26 Cancer Research Campaign Technology Ltd. Bioprecurseurs d'inhibiteurs de la tyrosine-kinase de proteines
US5981569A (en) * 1992-11-13 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease
US6217894B1 (en) * 1996-03-22 2001-04-17 Focal, Inc. Compliant tissue sealants
US20020068687A1 (en) * 1994-03-07 2002-06-06 Hui Chen Methods and compositions for inhibiting cell proliferative disorders
US20030060877A1 (en) * 2001-09-25 2003-03-27 Robert Falotico Coated medical devices for the treatment of vascular disease

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981569A (en) * 1992-11-13 1999-11-09 Yissum Research Development Company Of The Hebrew University Of Jerusalem Substituted phenylacrylonitrile compounds and compositions thereof for the treatment of disease
WO1995002420A2 (fr) * 1993-07-15 1995-01-26 Cancer Research Campaign Technology Ltd. Bioprecurseurs d'inhibiteurs de la tyrosine-kinase de proteines
US20020068687A1 (en) * 1994-03-07 2002-06-06 Hui Chen Methods and compositions for inhibiting cell proliferative disorders
US6217894B1 (en) * 1996-03-22 2001-04-17 Focal, Inc. Compliant tissue sealants
US20030060877A1 (en) * 2001-09-25 2003-03-27 Robert Falotico Coated medical devices for the treatment of vascular disease

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAYES-GENIS A. ET AL.: "The insuli-like growth factor axis", CIRCULATION RESEARCH, vol. 86, 2000, AM. HEART. ASSOC., USA, pages 125 - 130 *
BLUM G. ET AL.: "Substrate competitive inhibitors of IGF-1 receptor kinase", BIOCHEMISTRY, vol. 39, 2000, pages 15705 - 15712 *
GAZIT A. ET AL.: "Tyrphostins", J. MED. CHEM., vol. 34, 1991, pages 1896 - 1907 *
PARRIZAS M. ET AL.: "Specific inhibition of insulin-like growth factor-1 and insulin receptor tyrosine kinase activity and biological function by tyrphostins", ENDOCRINOLOGY, vol. 138, 1997, THE ENDOCRINE SOCIETY US, pages 1427 - 1433 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006087718A1 (fr) * 2005-02-17 2006-08-24 Yissum Research Development Company Of The Hebrew University Of Jerusalem Prolongement de duree de vie avec des medicaments

Similar Documents

Publication Publication Date Title
US6544541B1 (en) Devices and compounds for treating arterial restenosis
US9132099B2 (en) Medical implants and methods for regulating the tissue response to vascular closure devices
EP2061530B1 (fr) Dispositifs implantables contenant des ligands de récepteur nucléaire destinés au traitement de troubles vasculaires et d'autres troubles associés
EP2012794B1 (fr) Compositions et dispositifs intraluminaux permettant d'inhiber la stenose vasculaire
JP2009119257A (ja) 吸収可能なマトリックス材料および抗増殖薬を含む、血液透析血管アクセス及び他の血管移植片の機能不全を防止又は治療するための移植可能な装置および方法
US20090274739A1 (en) Methods and compositions for treating neointimal hyperplasia
JPH11510479A (ja) タモキシフェン類似体による心臓血管疾病の予防及び治療
TW200800196A (en) Compositions, systems, kits, and methods of administering rapamycin analogs with paclitaxel using medical devices
Tripathi et al. Prospects for epidermal growth factor in the management of corneal disorders
JP2019529567A (ja) アンレキサノクスの新たな使用
WO2001034132A2 (fr) Procedes pour le traitement, l'inhibition ou la prevention de modifications pathogenes resultant de lesions vasculaires a l'aide d'un antagoniste de l'aldosterone
AU2021238880A1 (en) Treatment methods
WO2005016333A1 (fr) Utilisation de tyrphostines pour traiter une resténose
Ielasi et al. One-year results following a pre-specified ABSORB implantation strategy in ST-elevation myocardial infarction (BVS STEMI STRATEGY-IT study)
JP4988131B2 (ja) 血小板のコラーゲンへの粘着を抑制するための新規な特異的機構
AU2004231345B2 (en) Use of steroid derivatives for the treatment of angiotensin II related disease e.g. cardiovascular and proliferative disorders
JP2006515291A (ja) ステントに入れて狭窄症を処置するための微小管安定化剤
Park et al. Inhibition of intimal hyperplasia by local perivascular application of rapamycin and imatinib mesilate after carotid balloon injury
US20220047584A1 (en) Method of treatment for infective endocarditis
Englesbe et al. I. AUTOLOGOUS VEIN GRAFT HEALING
HK1076387A1 (zh) 制备治疗免疫炎性疾病的联合药物的用途
HK1076387B (en) Use in the preparation of a combination medicament for the treatment or prevention of an immunoinflammatory disorder

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GM KE LS MW MZ NA SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase