WO2005099695A1 - Drug delivery systems for the prevention and treatment of vascular diseases - Google Patents

Drug delivery systems for the prevention and treatment of vascular diseases

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Publication number
WO2005099695A1
WO2005099695A1 PCT/EP2005/004117 EP2005004117W WO2005099695A1 WO 2005099695 A1 WO2005099695 A1 WO 2005099695A1 EP 2005004117 W EP2005004117 W EP 2005004117W WO 2005099695 A1 WO2005099695 A1 WO 2005099695A1
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compound
fadrozole
inhibitor
anti
method
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PCT/EP2005/004117
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French (fr)
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Margaret Forney Prescott
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Novartis Ag
Novartis Pharma Gmbh
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline

Abstract

The invention relates to the oral or local administration of fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active ingredients, and a device adapted for such local administration that results in inhibition of stenosis or restenosis following implantation of a stent or other vascular device or that inhibits vascular access dysfunction.

Description

DRUG DELIVERY SYSTEMS FOR THE PREVENTION AND TREATMENT OF VASCULAR DISEASES

The present invention relates to drug delivery systems for the prevention and treatment of diseases that occlude a lumen, particularly vascular diseases.

Many humans suffer from circulatory diseases caused by a progressive blockage of the blood vessels that perfuse the heart and other major organs. Severe blockage of blood vessels in such humans often leads to ischemic injury, hypertension, stroke or myocardial infarction. Atherosclerotic lesions which limit or obstruct coronary or peripheral blood flow are the major cause of ischemic disease related morbidity and mortality including coronary heart disease and stroke. To stop the disease process and prevent the more advanced disease states in which the cardiac muscle or other organs are compromised, medical revascularization procedures, such as percutaneous transluminal coronary angioplasty (PCTA), percutaneous transluminal angioplasty (PTA), atherectomy, bypass grafting or other types of vascular grafting procedures, are used.

Re-narrowing (restenosis) of an atherosclerotic coronary artery after various revascularization procedures occurs in 10-80% of patients undergoing this treatment, depending on the procedure used and the arterial site. Besides opening an artery obstructed by atherosclerosis, revascularization also injures endothelial cells and smooth muscle cells within the vessel wall, thus initiating a response that includes thrombosis, cell proliferation, inflammation and extracellular matrix production. Cell derived growth factors, such as platelet derived growth factor, infiltrating macrophages, leukocytes, lymphocytes or the smooth muscle cells themselves, provoke proliferative and migratory responses in the smooth muscle cells. Simultaneous with local smooth muscle cell proliferation and migration, inflammatory cells also invade the site of vascular injury and may migrate to the deeper layers of the vessel wall. Smooth muscle cell proliferation/migration usually begins within one to two days post-injury and, depending on the revascularization procedure used, continues for days and weeks, or even months.

Both cells within the atherosclerotic lesion and those within the media migrate, proliferate and/or secrete significant amounts of extracellular matrix proteins. Proliferation, migration and extracellular matrix synthesis continue until the damaged endothelial layer is completely repaired and normal nitric oxide synthesis is restored, at which time proliferation slows within the intima. The newly-formed tissue is called neointima, intimal thickening or restenotic lesion and usually results in narrowing of the vessel lumen. Extracellular matrix production within the vessel wall, especially the intima, includes the proteins collagen and elastin, as well as the proteoglycans perlecan, decorin, biglycan and versican. Further lumen narrowing may take place due to constructive remodeling, e.g., vascular remodeling, often with adventitial cell proliferation and/or contraction.

Alternatively, complications associated with vascular access treatment is a major cause of morbidity in many disease states. For example, vascular access dysfunction in hemodialysis patients is generally caused by outflow stenoses in the venous circulation. See Schwam et al., Kidney Int, Vol. 36, pp. 707-711 (1989). Vascular access related morbidity accounts for about 23% of all hospital stays for advanced renal disease patients and contributes to as much as half of all hospitalization costs for such patients. See Feldman, J Am Soc Nephrol, Vol. 7, pp. 523- 535 (1996).

Additionally, vascular access dysfunction in chemotherapy patients is generally caused by outflow stenoses in the venous circulation and results in a decreased ability to administer medications to cancer patients. Often the outflow stenoses is so severe as to require intervention.

Additionally, vascular access dysfunction in total parenteral nutrition (TPN) patients is generally caused by outflow stenoses in the venous circulation and results in reduced ability to care for these patients.

Up to the present time, there has not been any effective drug for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein in a mammal, particularly a human patient.

Survival of patients with chronic renal failure depends on optimal regular performance of dialysis. If this is not possible, e.g., as a result of vascular access dysfunction or failure, it leads to rapid clinical deterioration and unless the situation is remedied, these patients will die. Hemodialysis requires access to the circulation. The ideal form of hemodialysis vascular access should allow repeated access to the circulation, provide high blood flow rates, and be associated with minimal complications. At present, the three forms of vascular access are native arteriovenous fistulas (AVF), synthetic grafts and central venous catheters. Grafts are most commonly composed of polytetrafluoroethylene (PTFE) or Gore-Tex. Each type of access has its own advantages and disadvantages.

Vascular access dysfunction is the most important cause of morbidity and hospitalization in the hemodialysis population. Venous neointimal hyperplasia (VNH) characterized by stenosis and subsequent thrombosis accounts for the overwhelming majority of pathology resulting in dialysis graft failure. The most common form of vascular access procedure performed in chronic hemodialysis patients in the United States is the arteriovenous PTFE graft, which accounts for approximately 70% of all hemodialysis access.

Dr. Burnett S. Kelly and Col., Kidney Intl, Vol. 62; No. 6, p. 2272 (2002) and others have previously shown that VNH in the setting of arteriovenous hemodialysis grafts is characterized by smooth muscle cells, neointimal and adventitial microvessels and extracellular matrix components. However, despite a reasonable knowledge of the pathology of VNH, there are still no effective interventions for either the prevention or treatment of hemodialysis vascular access dysfunction. This is particularly unfortunate, as VNH in the setting of hemodialysis grafts appears to be a far more aggressive lesion as compared to the more common arterial neointimal hyperplasia that occurs in peripheral bypass grafts. Compare the 50% one-year primary patency in PTFE dialysis access grafts with an 88% five-year patency for aortoiliac grafts and a 70-80% one-year patency for femoro-popliteal grafts. Venous stenoses in the setting of dialysis access grafts also have a poorer response to angioplasty (40% three-month survival if thrombosed and a 50% six-month survival if not thrombosed) as compared to arterial stenoses. They believe that the lack of effective therapies for VNH and venous stenosis in dialysis grafts, such as PTFE dialysis grafts, is due to: (a) a lack of appreciation of the fact that venous stenosis may be very different from the more common arterial stenosis at the graft-artery anastomosis; and (b) a paucity of validated large animal models of VNH to test out novel interventions.

Despite the magnitude of the problem and the enormity of the cost, there are currently no effective therapies for the prevention or treatment of VNH in dialysis grafts.

Accordingly, there is a need for effective treatment and drug delivery systems for revascularization procedure, e.g., preventing and treating intimal thickening or restenosis that occurs after injury, e.g., vascular injury, including, e.g., surgical injury, e.g., revascularization- induced injury, e.g., also in heart or other grafts, or for the prevention or treatment of vascular access dysfunctions. It has now been found that fadrozole and fadrozole derivatives having aldosterone synthetase inhibiting properties, optionally in conjunction with other active compounds, e.g., anti- proliferative and/or anti-inflammatory compounds, have beneficial effects on above-mentioned disorders, diseases or dysfunctions.

Aldosterone synthetase is an enzyme which converts corticosterone to aldosterone to by hydroxylating cortocosterone to form 18-OH-corticosterone and 18-OH-corticosterone to aldosterone. The class of aldosterone synthetase inhibitors known to be applied for the treatment of hypertension and primary aldosteronism comprises both steroidal and non- steroidal aldosterone synthase inhibitors, the later being most preferred.

The class of aldosterone synthase inhibitors, collectively referred to herein as "aldosterone synthase inhibitors of the invention", comprises compounds having differing structural features. For example, mention may be made of the compounds which are selected from the group consisting of the non-steroidal aromatase inhibitors anastrozole, fadrozole (including the (+)- enantiomer thereof, as well as the steroidal aromatase inhibitor exemestane, the compounds disclosed in International Application No. PCT/EP2003/008720 published on February 19, 2004 as WO 04/14914 incorporated herein by reference in its entirety, co-pending application number EP 03/12851 filed November 17, 2003 incorporated herein by reference in its entirety or, in each case where applicable, a pharmaceutically acceptable salt thereof.

What is meant by fadrozole and a fadrozole derivative having aldosterone synthetase activity are the non-steroidal aldosterone synthase inhibitor which is the (+)-enantiomer of the hydrochloride of fadrozole (U.S. Patent Nos. 4,617,307 and 4,889,861) of formula (I)

HCI

and all related molecules mentioned in U.S. Patent Nos. 4,617,307 and 4,889,861 , or the pharmaceutically acceptable salt of such compounds, which are hereby incorporated by reference in their entirety.

According to the invention, the aldosterone synthase inhibitors of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties may be applied to an intravascular or extravascular arterial or venous device as the sole active ingredient or in conjunction with one or more active co-agents selected from (a) an immunosuppressive agent, e.g., a calcineurin inhibitor, e.g., a cyclosporin, e.g., cyclosporin A, ISA tx 247 or FK506; (b) a rapamycin derivative having mTOR inhibiting properties, such as, e.g., sirolimus, everolimus, ABT 578, Biolimus A9 or other limus compounds; (c) an EDG-receptor agonist having lymphocyte depleting properties, e.g., FTY720 (2-amino-2-[2-(4-octylphenyl)ethyl]propane-1 ,3-diol in free form or in a pharmaceutically acceptable salt form, e.g., the hydrochloride) or an analogue, such as described in WO 96/06068 or WO 98/45249, e.g., 2-amino-2-{2-[4-(1-oxo-5- pheny!pentyl)phenyl]ethyl}propane-1 ,3-diol or 2-amino-4-(4-heptyloxyphenyl)-2-methyl- butanol in free form or in a pharmaceutically acceptable salt form; (d) an anti-inflammatory agent, e.g., a steroid, e.g., a corticosteroid, e.g., dexamethasone or prednisone; an NSAID, e.g., a cyclooxygenase inhibitor, e.g., a cox-2 inhibitor, e.g., celecoxib, rofecoxib, etoricoxib or valdecoxib, e.g., a nuclear factor of activated T cells (NFAT) inhibitor, e.g., an ascomycin, e.g., ASM981 (or pimecrolimus), e.g., a cytokine inhibitor, e.g., an IL-1 , -2 or -6 inhibitor, e.g., pralnacasan or anakinra, e.g., a TNF inhibitor, e.g., Etanercept, e.g., a lymphokine inhibitor, e.g., a chemokine inhibitor, e.g., a nuclear factor kappa B (NF-kB) inhibitor, e.g., a tyrosine kinase inhibitor, such as imatinib (Gleevec/Glivec), e.g., a mast cell stabilizer, such as pemirolast; (e) an anti-thrombotic, anti-coagulant agent or anti-platelet agent, e.g., heparin or a glycoprotein llb/llla inhibitor, e.g., abciximab, eptifibatide or tirofibran; or an inhibitor of a coagulation factor, e.g., an Xa inhibitor, e.g., idrapariδnux, razaxaban, DX9065A, YM-150, LY-517717, DPC-423, BAY-59 or a direct thrombin inhibitor, e.g., ximelagatran or dabigatran; (f) an anti-proliferative agent, e.g., i. a microtubule stabilizing or destabilizing agent including, but not limited to, taxanes, e.g., taxol, paclitaxel or docetaxel; vinca alkaloids, e.g., vinblastine, especially vinblastine sulfate, vincristine especially vincristine sulfate, and vinorelbine; discodermolides or epothilones or a derivative thereof, e.g., epothilone B or a derivative thereof; a protein tyrosine kinase inhibitor, e.g., protein kinase C or Pl(3) kinase inhibitor, e.g., staurosporin; and related small molecules, e.g., midostaurin and related compounds disclosed in U.S. Patent No. 5,093,330, incorporated herein in its entirety, UCN-01 , BAY 43-9006, Bryostatin 1 , Perifosine, Limofosine, midostaurin, CGP52421 , RO318220, RO320432, GO 6976, Isis 3521 , LY333531 , LY379196, SU5416, SU6668, AG1296, imatinib, etc.; ii. a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, e.g., a N-phenyl-2-pyrimidine-amine derivative, e.g., imatinib, CT52923, RP-1776, GFB-111 , a pyrrolo[3,4-c]-beta-carboline-dione, etc.; iii. a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, e.g., EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF related ligands, and are in particular those compounds, proteins or monoclonal antibodies generically and specifically disclosed in WO 97/02266, e.g., the compound of example 39, or in EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837 063, U.S. Patent No. 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983 and, especially, WO 96/30347, e.g., compound known as CP 358774; WO 96/33980, e.g., compound ZD 1839, Iressa; and WO 95/03283, e.g., compound ZM105180, e.g., trastuzumab (HerpetinR), cetuximab, OSI-774, CI-1033, EKB-569, GW-2016, E1.1 , E2.4, E2.5, E6.2, E6.4, E2.11 , E6.3 or E7.6.3, retinoic acid, alpha (α)-, gamma (γ)- or delta (δ)-tocopherol or α-, γ- or δ-tocotrienol, or compounds affecting GRB2, IMC-C225; or

(g) a compound that inhibits angiogenesis, e.g., a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, e.g., proteins, small molecules or monoclonal antibodies generically and specifically disclosed in WO 98/35958, e.g., 1-(4-chloroanilino)-4-(4- pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g., the succinate, or in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819, WO 00/37502, WO 94/10202 and EP 0 769 947, those as described by Prewett et al., Cancer Res, Vol. 59, pp. 5209-5218 (1999); Yuan et al., Proc NatlAcad Sci USA, Vol. 93, pp. 14765-14770, (1996); Zhu et al., Cancer Res, Vol. 58, pp. 3209- 3214 (1998); and Mordenti et al., Toxicol Pathol, Vol. 27, No. 1 , pp. 14-21 (1999); Angiostatin™, described by O'Reilly et al., Cell, Vol. 79, pp. 315-328 (1994); Endostatin™, described by O'Reilly et al., Cell, Vol. 88, pp. 277-285 (1997); anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti- VEGF receptor antibodies, e.g., RhuMab; (h) a statin, e.g., having HMG-CoA reductase inhibition activity, e.g., fluvastatin, lovastatin, simvastatin, pravastatin, atorvastatin, cerivastatin, pitavastatin, rosuvastatin or nivastatin; (i) a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, e.g., FGF, IGF; (j) a matrix metalloproteinase inhibitor, e.g., batimistat, marimistat, trocade, CGS 27023, RS 130830 or AG3340; (k) a modulator, i.e., antagonists or agonists, of kinases, e.g., JNK, ERK1/2, MAPK or STAT; (I) a compound stimulating the release of (NO) or a NO donor, e.g., diazeniumdiolates, S-nitrosothiols, mesoionic oxatriazoles, isosorbide or a combination thereof, e.g., mononitrate and/or dinitrate; (m) a somatostatin analogue, e.g., octreotide, lanreotide, vapreotide or a cyclohexapeptide having somatostatin agonist properties, e.g., cyclo[4-(NH2-C2H -NH- CO-O)Pro-Phg-DTrp-Lys-Tyr(Bzl)-Phe]; or a modified GH analogue chemically linked to PEG, e.g., Pegvisomant; (n) a compound inhibiting the renin-angiotensin system, e.g., a renin inhibitor, e.g., SPP100; an ACE inhibitor, e.g., captopril, enalapril, lisinopril, fosinopril, benazepril, quinapril, ramipril, imidapril, perindopril erbumine, trandolapril or moexipril; or an ACE receptor blocker, e.g., losartan, irbesartan, candesartan cilexetil, valsartan or olmesartan medoxomil; or (o) mycophenolic acid or a salt thereof, e.g., sodium mycophenolate; or a prodrug thereof, e.g., mycophenolate mofetil.

Comprised also in the above list the pharmaceutically acceptable salts, the corresponding racemates, diastereoisomers, enantiomers, tautomers, as well as the corresponding crystal modifications of above disclosed compounds where present, e.g., solvates, hydrates and polymorphs.

By antibody is meant monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibodies fragments so long as they exhibit the desired biological activity. A pharmaceutical combination comprising an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase properties also form part of the present invention.

The pharmaceutical compositions according to the invention are those suitable for enteral, such as oral or rectal, transdermal and parenteral administration to mammals, including man, to inhibit aldosterone synthase. The said pharmaceutical compositions comprise a therapeutically effective amount of a pharmacologically active aldosterone synthase inhibitor of the invention, alone or in combination with one or more pharmaceutically acceptable carriers.

The pharmacologically active compounds of the invention are useful in the manufacture of pharmaceutical compositions comprising a therapeutically effective amount thereof in conjunction or admixture with excipients or carriers suitable for either enteral or parenteral application. Preferred are tablets and gelatin capsules comprising the active ingredient together with diluents, e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine; lubricants, e.g., silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethyleneglycol; for tablets also binders, e.g., magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if desired disintegrants, e.g., starches, agar, alginic acid or its sodium salt, or effervescent mixtures; and/or absorbants, colorants, flavors and sweeteners.

According to the invention, an aldosterone synthase inhibitor of the invention, preferably fadrozole is preferably locally administered or delivered in conjunction with one or more co- agents selected from (a)-(n), a cox-2 inhibitor, a cytokine inhibitor or a chemokine inhibitor, delivered locally as defined above. An aldosterone synthase inhibitor of the invention, preferably fadrozole is delivered orally to provide additive anti-resentotic, anti-fibrotic activity to a drug eluting stent or other intravascular or extravascular local delivery device eluting a compound described in (a)-(n) or a cox-2 inhibitor, a cytokine inhibitor or a chemokine inhibitor.

In accordance with the particular findings of the present invention, there is provided:

1.1 A method for preventing or treating increased extracellular matrix deposition in a subject in need thereof, comprising local or oral administration of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above. Use of an aldosterone synthase inhibitor (preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties ) for the preparation of a medicament for preventing or treating increased extracellular matrix deposition. Use as described herein wherein the aldosterone synthase inhibitor is delivered via controlled delivery from a catheter-based device or an intraluminal medical device.

1.2 A method for the prevention or treatment of intimal thickening in vessel walls comprising oral or controlled delivery from any catheter-based device, intraluminal medical device or adventitial medical device of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above. Use of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties to prepare a medicament for the prevention or treatment of intimal thickening in vessel walls, comprising e.g. oral or controlled delivery from any catheter-based device, intraluminal medical device or adventitial medical device. Preferably the intimal thickening in vessel walls is stenosis; restenosis, e.g., following revascularization or neovascularization; and/or inflammation and/or thrombosis.

1.3 A method or use as defined in 1.1 and 1.2 associated, simultaneously or sequentially, with the administration of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a derivative thereof having aldosterone synthetase inhibiting properties, e.g. a compound of formula (I). Preferably fadrozole or the derivative thereof, e.g., of formula (I), is administered orally. Alternatively, a method or use as defined in 1.1-1.2 may be associated, simultaneously or sequentially, with the administration of a therapeutically effective amount of the co-agent.

1.4 A method for preventing or treating restenosis in diabetic or non-diabetic patients implanted with a vascular device comprising administering to said patients a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above.

1.5 A method for preventing or treating restenosis in diabetic or non-diabetic patients comprising the controlled delivery from any catheter-based device, intraluminal medical device or adventitial medical device of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, as monotherapy or optionally in conjunction with one or more other active co-agents, e.g., as disclosed above.

1.6 A method comprising a combination of method steps as disclosed above under 1.4 and 1.5.

1.1 A method for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter, preferably a large bore catheter, into a vein or artery, or actual treatment, in a subject in need thereof, which comprises administering to the subject an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above; or a controlled delivery from a drug delivery medical device or system of a therapeutically effective amount of fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above. Preferably the invention relates to the prevention or reduction of vascular access dysfunction in hemodialysis.

1.8 A method for the prevention or treatment of anastomic hyperplasia in a subject comprising the controlled delivery from any catheter-based device, intraluminal medical device or adventitial medical device of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above.

1.9 A method for the prevention or treatment of arterial, e.g., aortic, by-pass anastomosis in a subject comprising the controlled delivery from any catheter-based device, intraluminal medical device or adventitial medical device of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in conjunction with one or more other active co-agents, e.g., as disclosed above. 1.10 A method as defined in 1.7-1.9 associated, simultaneously or sequentially, with the administration of a therapeutically effective amount of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a derivative thereof, e.g., a compound of formula (I). Preferably fadrozole or the derivative thereof, e.g., of formula (I), is administered orally. Alternatively, a method as defined in 1.7-1.9 may be associated, simultaneously or sequentially, with the administration of a therapeutically effective amount of the co-agent.

2.1 A drug delivery device or system comprising: i) a medical device adapted for local application or administration in hollow tubes, e.g., a catheter-based delivery device or a medical device intraluminal or outside of hollow tubes, such as an implant or a sheath placed within the adventitia; and ii) a therapeutic dosage of an aldosterone synthase inhibitor of the invention, preferably a fadrozole derivative having aldosterone synthetase inhibiting properties or fadrozole, optionally in conjunction with a therapeutic dosage of one or more other active co-agents, e.g., as disclosed above, each being releasably affixed to the delivery device or system.

2.2 A device as defined herein for use in any method as defined under 1.1-1.10.

3.1 Use of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties in any of the method as defined under 1.4 or 1.10 optionally in conjunction with one or more other active co-agent, or in the manufacture of a medicament for use in any of the method as defined under 1.4 or 1.10 optionally in conjunction with one or more other active co-agent.

3.2 Use of an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, optionally in combination with an active co-agent as defined herein, in the manufacture of a device as defined herein for use in any method as defined under 1.1-1.10.

3.3 Use of indwelling shunt, fistula or catheter coated by, impregnated with or incorporating an aldosterone synthase inhibitor of the invention, preferably fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties, i.e., being releasably affixed to the medical device, as described herein, for the manufacture of a medicament for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein or artery, in a subject in need thereof.

3.4 Use of a device as defined in 3.1 , for the manufacture of a medicament for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein or artery, in a subject in need thereof. Preferably for the prevention or reduction of stenosis, restenosis and/or hyperplasia, preferably in diabetic patients.

4. A pharmaceutical composition for use in any method as defined under 1.4 or 1.7 comprising an aldosterone synthase inhibitor of the invention, preferably fadrozole or a derivative thereof having aldosterone synthetase properties, together with one or more pharmaceutically acceptable diluents or carriers therefor.

Method or use as defined in 1.1 to 1.4, method as defined in 1.4 to 1.10, a device as defined in 2.1 to 2.2, a use as defined in 3.1 to 3.3, and a composition as defined in 4., wherein the aldosterone synthase inhibitor is fadrozole or the derivative thereof, preferably of formula (I).

A local delivery device or system according to the invention can be used to reduce stenosis or restenosis as an adjunct to revascularization, bypass or grafting procedures performed in any vascular location including coronary arteries, carotid arteries, renal arteries, peripheral arteries, cerebral arteries or any other arterial or venous location, to reduce anastomic stenosis or hyperplasia including in the case of arterial-venous dialysis access with or without PTFE or, e.g., Gore-Tex grafting and with or without stenting, or in conjunction with any other heart or transplantation procedures, or congenital vascular interventions.

An aldosterone synthase inhibitor of the invention, preferably fadrozole or fadrozole derivative having aldosterone synthetase inhibiting properties will be referred to hereinafter as "active agent". "Drug(s)" means active agent or the active agent and the active co-agent.

The local administration preferably takes place at or near the lesion sites, e.g., vascular lesion sites.

The local administration may be by one or more of the following routes: via any catheter-based or other intravascular delivery system including, but not limited to, stents, intranasally, intrabronchially, interperitoneally or eosophagal, or via delivery devices used in the musculature. Hollow tubes include natural body vessels or ducts, e.g., circulatory system vessels, such as blood vessels (arteries or veins); tissue lumen; lymphatic pathways; digestive tract including alimentary duct, e.g., esophagus or biliary ducts; respiratory tract, e.g., trachea; excretory system tubes, e.g., intestines, ureters or urethra-prostate; reproductive system tubes and ducts; body cavity tubes, etc. Local administration or application of the drug(s) may afford concentrated delivery of said drug(s), achieving tissue levels in target tissues not otherwise obtainable through other administration route. Additionally local administration or application may reduce the risk of remote or systemic toxicity. Preferably the smooth muscle cell proliferation or migration is inhibited or reduced according to the invention immediately proximal or distal to the locally treated or stented area.

Means for local delivery of the drug(s) to hollow tubes can be by physical delivery of the drug(s) either internally or externally to the hollow tube. Local drug(s) delivery includes catheter delivery systems, local injection devices or systems or indwelling devices. Such devices or systems would include, but not be limited to, stents, coated stents, endolumenal sleeves, stent- grafts, sheathes, balloons, liposomes, controlled-release matrices, polymeric endoluminal paving or other endovascular devices, embolic delivery particles, cell targeting, such as affinity based delivery, internal patches around the hollow tube, external patches around the hollow tube, hollow tube cuff, external paving, external stent sleeves, external wraps and the like. See Eccleston et al., Interventional Cardiol Monitor, Vol. 1 , pp. 33-40-41 (1995); Interventional Cardiol, Vol. 1 , pp. 103-116 (1996); or Regar, Sianos and Serruys, Br Med Bull, Vol. 59, pp. 227-248 (2001), which disclosures are herein incorporated by reference.

Preferably the delivery device or system fulfils pharmacological, pharmacokinetic and mechanical requirements. Preferably it also is suitable for sterilization.

The stent according to the invention can be any stent including self-expanding stent, or a stent that is radially expandable by inflating a balloon or expanded by an expansion member, or a stent that is expanded by the use of radio frequency which provides heat to cause the stent to change its size. A stent composed of or coated with a polymer or other biocompatible materials, e.g., porous ceramic, e.g., nanoporous ceramic, into which the drug(s) has been impregnated or incorporated can be used. Stents can be biodegradable or can be made of metal or alloy including, but not limited to, Cr, Co, Ni, Ti, gold or another stable substance when intended for permanent use. The drug(s) may also be entrapped into the metal of the stent or graft body which has been modified to contain micropores or channels. Also lumenal and/or ablumenal coating or external sleeve or wrap made of polymer or other biocompatible materials, e.g., as disclosed below, that contain the drug(s) can also be used for local delivery. By "biocompatible" is meant a material which elicits no or minimal negative tissue reaction including, e.g., thrombus formation and/or inflammation.

Stents may commonly be used as a tubular structure left inside the lumen of a duct to relieve an obstruction. They may be inserted into the duct lumen in a non-expanded form and are then expanded autonomously (self-expanding stents) or with the aid of a second device in situ, e.g., a catheter-mounted angioplasty balloon which is inflated within the stenosed vessel or body passageway in order to shear and disrupt the obstructions associated with the wall components of the vessel and to obtain an enlarged lumen. Alternatively, stents being easily deformed at lower temperature to be inserted in the hollow tubes may be used: after deployment at site, such stents recover their original shape and exert a retentive and gentle force on the internal wall of the hollow tubes, e.g., of the esophagus or trachea.

The drug(s) may be incorporated into or affixed to the stent in a number of ways and utilizing any biocompatible materials; it may be incorporated into, e.g., a polymer or a polymeric matrix and sprayed onto the outer surface of the stent. A mixture of the drug(s) and the polymeric material may be prepared in a solvent or a mixture of solvents and applied to the surfaces of the stents also by dip-coating, brush coating and/or dip/spin coating, the solvent (s) being allowed to evaporate to leave a film with entrapped drug(s). In the case of stents where the drug(s) is delivered from micropores, struts or channels, a solution of a polymer may additionally be applied as an outlayer to control the drug(s) release; alternatively, the active agent may be comprised in the micropores, struts or channels and the active co-agent may be incorporated in the outlayer, or vice versa. The active agent may also be affixed in an inner layer of the stent and the active co-agent in an outer layer, or vice versa. The drug(s) may also be attached by a covalent bond, e.g., esters, amides or anhydrides, to the stent surface, involving chemical derivatization. The drug(s) may also be incorporated into a biocompatible porous ceramic coating, e.g., a nanoporous ceramic coating. The medical device of the invention is configured to release the active co-agent concurrent with or subsequent to the release of the active agent.

Examples of polymeric materials include hydrophilic, hydrophobic or biocompatible biodegradable materials, e.g., polycarboxylic acids; cellulosic polymers; starch; collagen; hyaluronic acid; gelatin; lactone-based polyesters or copolyesters, e.g., polylactide; polyglycolide; polylactide-glycolide; polycaprolactone; polycaprolactone-glycolide; poly(hydroxybutyrate); poly(hydroxyvalerate); polyhydroxy(butyrate-co-valerate); polyglycolide- co-trimethylene carbonate; poly(diaxanone); polyorthoesters; polyanhydrides; polyaminoacids; polysaccharides; polyphospoeters; polyphosphoester-urethane; polycyanoacrylates; polyphosphazenes; poly(ether-ester) copolymers, e.g., PEO-PLLA, fibrin; fibrinogen; or mixtures thereof; and biocompatible non-degrading materials, e.g., polyurethane; polyolefins; polyesters; polyamides; polycaprolactame; polyimide; polyvinyl chloride; polyvinyl methyl ether; polyvinyl alcohol or vinyl alcohol/olefin copolymers, e.g., vinyl alcohol/ethylene copolymers; polyacrylonitrile; polystyrene copolymers of vinyl monomers with olefins, e.g., styrene acrylonitrile copolymers; ethylene methyl methacrylate copolymers; polydimethylsiloxane; poly(ethylene-vinylacetate); acrylate based polymers or coplymers, e.g., polybutylmethacrylate, poly(hydroxyethyl methylmethacrylate); polyvinyl pyrrolidinone; fluorinated polymers, such as polytetrafluoethylene; cellulose esters, e.g., cellulose acetate, cellulose nitrate or cellulose propionate; or mixtures thereof.

When a polymeric matrix is used, it may comprise two layers, e.g., a base layer in which the drug(s) is/are incorporated, e.g., ethylene-co-vinylacetate and polybutylmethacrylate, and a top coat, e.g., polybutylmethacrylate, which is drug(s)-free and acts as a diffusion-control of the drug(s). Alternatively, the active agent may be comprised in the base layer and the active co- agent may be incorporated in the outlayer, or vice versa. Total thickness of the polymeric matrix may be from about 1-20 μ or greater.

According to the method of the invention or in the device or system of the invention, the drug(s) may elute passively, actively or under activation, e.g., light-activation.

The drug(s) elutes from the polymeric material or the stent over time and enters the surrounding tissue, e.g., up to ca. one month to one year. The local delivery according to the present invention allows for high concentration of the drug(s) at the disease site with low concentration of circulating compound. The amount of drug(s) used for local delivery applications will vary depending on the compounds used, the condition to be treated and the desired effect. For purposes of the invention, a therapeutically effective amount will be administered, e.g., the drug delivery device or system is configured to release the active agent and/or the active co-agent at a rate of 0.01-200 μg/day with the rate likely to vary by day following implantation. By therapeutically effective amount is intended an amount sufficient to inhibit extracellular matrix synthesis and deposition and resulting in the prevention and treatment of the disease state. Specifically, for the prevention or treatment of restenosis, e.g., after revascularization, or for the prevention or treatment of vascular access dysfunction local delivery may require less compound than systemic administration. A contemplated treatment period for use in the prevention or reduction of vascular access dysfunction of the present invention is about 120 days, e.g., 80 days, preferably 60 days, e.g., 28 days, more preferably 28 days in association with the insertion or repair of an indwelling shunt, fistula or catheter or actual treatment.

A preferred method of use in the prevention or reduction of vascular access dysfunction is a method for preventing or reducing vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling access clotting shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in dialysis patients.

A preferred method of use in the prevention or reduction of vascular access dysfunction is a method for preventing or reducing vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in cancer patients.

A preferred method of use in the prevention or reduction of vascular access dysfunction is a method for preventing or reducing vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter associated with insertion or repair of the indwelling shunt, fistula or catheter, or actual treatment, in TPN patients.

By "prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter", as used herein, is meant that the incidence of vascular thrombosis and/or fistula failure and/or shunt failure and/or vascular access clotting and/or stenosis and/or restenosis and/or the need for declotting an indwelling vascular access shunt, fistula or catheter in patients treated according to the invention collected over the observation period are prevented or reduced in comparison to untreated patients.

By "in association with the insertion or repair of an indwelling shunt, fistula or catheter", as used herein, is meant that the treatment according to the invention can commence immediately, for example within 4-8 hours, after insertion or repair of the indwelling shunt, fistula or catheter or actual treatment, such as dialysis treatment; within a few days, e.g., about 7 days, preferably about 1 or 2 days, after insertion or repair of the indwelling shunt, fistula or catheter or actual treatment, such as dialysis treatment; or for a period of days, e.g., about 30 days, preferably about 14 days, preferably about 7 days, prior to insertion or repair of the indwelling shunt, fistula or catheter or actual treatment, such as dialysis treatment. Also contemplated within the phrase "in association with the insertion or repair of an indwelling shunt, fistula or catheter" is a dosing protocol in which a dose or several doses, are skipped, e.g., in the morning of or on the day of insertion, repair or treatment. Also contemplated within the phrase "in association with the insertion or repair of an indwelling shunt, fistula or catheter" is a dosing protocol in which a day of drug treatment or several days of drug treatment, are skipped.

Included in term "treatment", when used herein to refer surgical procedures, are procedures selected from access surgery, placement of fistula or shunt, catheter insertion, actual disease treatment, such as dialysis treatment, and declotting of an access shunt, fistula or catheter. Further, treatment for insertion access also includes repair/revision of the access. For example, a patient experiencing a failure in a dialysis access shunt will have the access repaired, for instance, by angioplasty.

By the term "collected over the observation period", as used herein, means a period of up to or about 12 months, preferably 12 months.

When fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties is administered systemically or is additionally administered by systemic application, e.g., in the prevention or reduction of vascular access dysfunction, according to the invention, daily dosages required in practicing the method of the present invention will vary depending upon, e.g., the compound used, the host, the mode of administration and the severity of the condition to be treated. A preferred daily dosage range is about from 0.1-32 mg as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from, e.g., 0.1-32 mg p.o. The compound may be administered by any conventional route, in particular, enterally, e.g., orally, e.g., in the form of tablets, capsules, drink solutions, nasally, pulmonary (by inhalation) or parenterally, e.g., in the form of injectable solutions or suspensions. Suitable unit dosage forms for oral administration comprise from ca. 0.05-32 mg, usually 2-16 mg compound, together with one or more pharmaceutically acceptable diluents or carriers therefor.

Preferred combinations according to the invention are those comprising a compound of formula (I) in conjunction or association with a compound having anti-proliferative properties, e.g., taxol; paclitaxel; docetaxel; an epothilone; a tyrosine kinase inhibitor, e.g., a protein kinase C or Pl(3) kinase inhibitor, e.g., staurosporin or a related small molecule; a PDGF receptor tyrosine kinase inhibitor; a PDGF receptor inhibitor; a compound binding to PDGF, e.g., imatinib; a VEGF receptor tyrosine kinase inhibitor; a VEGF receptor inhibitor; a compound binding to VEGF, e.g., 1-(4-chloroaniIino)-4-(4-pyridylmethyl)phtalazine; a cox-2 inhibitor; an ascomycin, e.g., pimecrolimus; or a calcineurin inhibitor, e.g., CysA, ISA tx 247 or FK506. A combination of fadrozole or a fadrozole derivative as mentioned above with a compound having anti-inflammatory properties, pimecrolimus or an EDG-receptor agonist having lymphocyte depleting properties, has particularly beneficial effects when used in the treatment or prevention of restenosis in diabetic or non-diabetic patients. A combination of fadrozole or a fadrozole derivative as mentioned above with a statin or an aldosterone synthetase inhibitor or an aldosterone receptor blocker, or with a compound inhibiting the renin-angiotensin system has also beneficial properties; such a combination also forms part of the invention.

An aldosterone synthase inhibitor of the invention, preferably fadrozole or the fadrozole derivative having aldosterone synthetase inhibiting properties may also be applied to the drug delivery device or system in admixture with an antioxidant, e.g., 2,6-di-terf-butyI-4- methylphenol, e.g., at an amount up to 0.5% by weight, preferably 0.2% by weight.

Utility of the drug(s) may be demonstrated in animal test methods as well as in clinic, e.g., in accordance with the methods hereinafter described.

A1. Inhibition of late stage neointimal lesion progression a rat carotid artery balloon injury model Numerous compounds have been shown to inhibit intimal lesion formation at two weeks in the rat ballooned carotid model, while only few compounds prove effective at four weeks, and even fewer compounds inhibit late stages of lesion development using a model in which balloon injury occurs one or more weeks prior to commencement of treatment, the time during which extracellular matrix synthesis and deposition is a major mechanism of intimal lesion formation. Compounds of formula (I) were tested in the following rat model.

Rats were dosed via subcutaneously implanted osmotic mini-pumps filled with vehicle (control) or with a compound of formula (I) solubilized in the vehicle used in the control group. Mini-pump implantation was performed at 15 days following balloon injury surgery with vehicle or compound delivery occurring between days 15 and 49 days following balloon injury. Rat carotid arteries were balloon injured using a method described by Clowes et al., Lab Invest, Vol. 49, pp. 208-215 (1983). Following sacrifice at 49 days post-balloon injury, carotid arteries were removed and processed for histologic and morphometric evaluation. In this assay, the compounds of formula (I), e.g., 40-O-(2- hydroxyethyl)-fadrozole, reduced neointimal lesion formation at 49 days (seven weeks) following balloon injury when administered at a dose of from 0.04-0.4 mg/kg/day. For example, for 40-O-(2-hydroxyethyl)-fadrozole administered at 0.4 mg/kg/day, the percent of intimal lesion inhibition at 49 days was 25%. Compounds of formula (I), e.g., 40-O-(2- hydroxyethyl)-fadrozole, have the beneficial effect to inhibit intimal lesions developing between two and at seven weeks post-ballooning.

A2. Inhibition of restenosis at 28 days in the rabbit iliac stent model Compounds of formula (I), e.g., fadrozole, were tested in the following rat model. A combined angioplasty and stenting procedure was performed in New Zealand White rabbit iliac arteries. Iliac artery balloon injury was performed by inflating a 3.0 x 9.0 mm angioplasty balloon in the mid-portion of the artery followed by "pull-back" of the catheter for one balloon length. Balloon injury was repeated two times, and a 3.0 x 12 mm stent was deployed at 6 atm for 30 seconds in the iliac artery. Balloon injury and stent placement was then performed on the contralateral iliac artery in the same manner. A post-stent deployment angiogram was performed. All animals received oral aspirin 40 mg/day daily as anti-platelet therapy and were fed standard low-cholesterol rabbit chow. Three groups of rabbits were orally gavaged daily with vehicle or a compound of formula (I) at two doses, e.g., 4 mg/kg/day or 8 mg/kg/day. Each treatment group consisted of nine rabbits with two stents implanted per rabbit. Twenty-eight days after stenting, animals were anesthetized, and a pre-euthanasia angiogram of the iliac arteries was completed followed by euthanasia and perfusion-fixation. The stented arteries were embedded in methylmethacrylate with sections taken from the proximal, middle and distal portions of each stent. A 3-mm arterial segment just proximal and distal to the stents was processed and stained to evaluate edge effects. All sections were stained with H&E and Movat pentachrome stain. To assess cellular proliferation, animals received bromodeoxyuridine (BrdU) before euthanasia. To access collagen deposition, selection sections were stained with Sirius-red. Computerized planimetry was s performed to determine the area of the internal elastic lamina (IEL), external elastic lamina (EEL) and lumen. The neointima and neointimal thickness was measured both at and between the stent struts. The vessel area was measured as the area within the EEL. Data were expressed as mean ± SEM. Statistical analysis of the histologic data was accomplished using analysis of variance (ANOVA) due to the fact that two stented arteries are measured per animal with a mean generated per animal. A P<0.05 was considered statistically significant. To evaluate stent endothelialization, an additional two rabbits per treatment group rabbits underwent stenting, as described above, and were dosed with placebo or compounds of formula (I), e.g., fadrozole, at either 4 mg/kg/day or 8 mg/kg/day orally. Dosing for 28 days was followed by scanning electron microscopy of longitudinally cut stents. In this model, the treatment with the compound of formula (I) resulted in a significant reduction in the extent of restenotic lesion formation, e.g., the treatment with fadrozole at both 4 mg/kg/day and 8 mg/kg/day produced a significant (P<0.03) reduction in neointimal thickness, neointimal area and percent arterial stenosis, with extent of lesion inhibition similar at the 4 mg/kg/day and the 8 mg/kg/day doses. Smooth muscle cell density was not reduced in the treated animals compared to placebo-treated controls, consistent with fadrozole exerting intimal lesion effects via a reduction in extracellular matrix synthesis and deposition. Sirius red staining demonstrated less collagen deposition in neotima of fadrozole treated rabbits. There was extensive neointimal formation in placebo-treated animals at 28 days, with the lesions consisting of abundant smooth muscle cells in extracellular matrix. Endothelial healing at 28 days was similar in fadrozole-treated animals, at both doses and controls. Re-endothelialization was 90- 100%, with similar values observed in the stented sections of rabbits treated with vehicle and fadrozole.

A3. Treatment of angina pectoris patients Twenty-five patients with angina pectoris are treated with a stent according to the invention, e.g., delivering a fadrozole derivative having aldosterone synthetase inhibiting properties. The stents (10-35 mm) are delivered to the patients (2.5-4.0 mm vessel calibre) and the patients are discharged without clinical complications. At four months, intravascular ultrasound and four months and one year angiographic follow-up, no significant restenosis is detected. In this trial, when a stent delivering fadrozole or a derivative thereof having aldosterone synthetase inhibiting properties in conjunction with an mTOR inhibiting compound, e.g., everolimus or an anti-inflammatory compound, e.g., pimecrolimus or a protein kinase inhibitor, e.g., midostaurin or a PDGF inhibiting compound, e.g., imatinib is used, beneficials effects are obtained.

A4. Prevention or reduction of vascular access dysfunction in association with the insertion of an indwelling catheter into the vein of a patient One hundred fifty prospective dialysis patients, who undergo successful insertion of an indwelling, large bore catheter, into a vein are selected for the study. The catheter may be impregnated with and eluting fadrozole. These patients are divided into two groups, and both groups do not differ significantly with sex, distribution of vascular condition or condition of lesions after insertion. One group (about 50 patients) receives fadrozole or a fadrozole derivative having aldosterone synthetase inhibiting properties in a daily dose of 0.75-32 mg, hereinafter identified as group 1, and another group (about 100 patients) does not receive the compound to be tested, hereinafter identified as group H. In addition, patients may also be given a calcium antagonist, nitrates and/or anti-platelet agents. These drugs are administered for three to six consecutive months following catheter insertion. The comparative clinical data collected over the observation period of six months demonstrate the efficacy of three-month treatment with fadrozole or a fadrozole derivative, e.g., 40-O-(2-hydroxyethyl)-fadrozole, for the prevention or reduction of vascular access dysfunction in patients after catheter insertion.

The following examples are illustrative of the invention without limiting it.

Example 1

The stent is manufactured from medical cobalt alloy and is composed of a series of cylindrically oriented rings and connecting bars aligned along a common longitudinal axis. The stent is pre- mounted on a delivery system. The active agent, e.g., fadrozole (25-100%), is incorporated into a polymer matrix based on a semi-crystalline ethylene-vinyl alcohol copolymer. The stent is coated with this matrix.

Example 2

A stent is weighed and then mounted for coating. While the stent is rotating, a solution of polylactide glycolide, fadrozole, 0.7 mg/mL 2,6-di-fer.-butyl-4-methylphenol and 1 mg/mL everolimus dissolved in a mixture of methanol and tetrahydrofuran, is sprayed onto it. The coated stent is removed from the spray and allowed to air-dry. After a final weighing, the amount of coating on the stent is determined.

The everolimus or another compound inhibiting mTOR, such as sirolimus or ABT578 or Biolimus A9 other limus, may be replaced by taxol, paclitaxel, a tyrosine kinase inhibitor, a protein kinase C inhibitor, a VEGF receptor tyrosine kinase inhibitor, a VEGF receptor inhibitor, a compound binding to VEGF, an aldosterone receptor blocker, a compound inhibiting the renin-angiotensin system or an anti-inflammatory compound.

Example 3

Four 25 mm pieces of coated stents as described above are placed into 100 mL of phosphate buffer solution (PBS) having a pH of 7.4. Another four pieces from each series are placed into 100 mL polyethylene glycol (PEG)/water solution (40/60 v/v, MW of PEG = 400). The stent pieces are incubated at 37°C in a shaker. The buffer and PEG solutions are changed daily and different assays are performed on the solution to determine the released fadrozole concentrations. Such assays can show a stable release of fadrozole from coated stents for more than 20 days. By the term "stable release of fadrozole" is meant less than 10% of variation of the drug release. Controlled-release techniques used by a person skilled in the art allow an unexpected easy adaptation of the required drug release rate. Thus, by selecting appropriate amounts of reactants in the coating mixture it is possible to easily control the bioeffectiveness of the fadrozole or fadrozole derivative coated stents.

Claims

1. A method for preventing or treating increased extracellular matrix deposition in a mammal in need thereof, comprising oral or local administration of a therapeutically effective amount of a pharmaceutical composition comprising an aldosterone synthase inhibitor.
2. Use of an aldosterone synthase inhibitor for the preparation of a medicament for preventing or treating increased extracellular matrix deposition.
3. The method of Claim 1 or use of Claim 2, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative, or the pharmaceutically acceptable salt of such a compound.
4. The method of Claim 1 , or the use of claim 2, wherein fadrozole is a compound of formula (I)
HCI
5. The method of Claim 3 or use of Claim 3, wherein fadrozole is the (+) enantiomer.
6. A method for the treatment of intimal thickening in vessel walls comprising oral delivery or controlled delivery from a catheter-based device or an intraluminal medical device of a therapeutically effective amount of a pharmaceutical composition comprising an aldosterone synthase inhibitor.
7. Use of an aldosterone synthase inhibitor, to prepare a medicament for the prevention or treatment of intimal thickening in vessel walls.
8. The method of Claim 6 or the use of claim 7, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative, or the pharmaceutically acceptable salt of such a compound.
9. The method of Claim 8 or use of Claim 8, wherein fadrozole is a compound of formula (I)
10. The method of Claim 9 or use of Claim 9, wherein fadrozole is the (+) enantiomer.
11. Use according to any of claims 2 to 10 wherein the aldosterone synthase inhibitor is delivered via controlled delivery from a catheter-based device or an intraluminal medical device.
12. The method of Claim 1 or the use of any of Claims 2 or 11 , wherein fadrozole or a fadrozole derivative is administered or delivered in conjunction with one or more other active ingredients selected from a rapmycin derivative having mTOR inhibiting properties, a calcineurin inhibitor, an EDG receptor agonist, an anti-inflammatory agent, an anti-thrombotic, anti-platelet or anti-coagulant agent, an anti-proliferative agent, a protein kinase C inhibitor, a microtubule stabilizing or destabilizing agent, a tyrosine kinase inhibitor, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, a statin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, a modulator (i.e., antagonists or agonists) of kinases, or a compound stimulating the release of (NO) or a NO donor.
13. The method of Claim 6 or the use of any of claims 7 or 11 , wherein fadrozole or a fadrozole derivative is administered or delivered in conjunction with one or more other active ingredients selected from a rapamycin derivative having mTOR inhibiting properties, a calcineurin inhibitor, an EDG receptor agonist, an anti-inflammatory agent, an anti-thrombotic or anti-coagulant agent, an anti-proliferative agent, a protein kinase C inhibitor, a microtubule stabilizing or destabilizing agent, a tyrosine kinase inhibitor, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, a statin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, a modulator (i.e., antagonists or agonists) of kinases, or a compound stimulating the release of (NO) or a NO donor.
14. A drug delivery device or system comprising: (a) a medical device adapted for local application or administration in hollow tubes, e.g., a catheter-based delivery device or an intraluminal medical device; and (b) a therapeutic dosage of an aldosterone synthase inhibitor being releasably affixed to the medical device.
15. The drug delivery device or system of Claim 14, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative.
16. A device according to Claim 14 comprising a therapeutic dosage of an aldosterone synthase inhibitor in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a rapamycin derivative having mTOR inhibiting properties, a calcineurin inhibitor, an EDG receptor agonist, an anti-inflammatory agent, an anti-thrombotic, anti-platelet or anti-coagulant agent, an anti-proliferative agent, a protein kinase C inhibitor, a microtubule stabilizing or destabilizing agent, a tyrosine kinase inhibitor, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, a statin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, an inhibitor of a modulator (i.e., antagonists or agonists) of kinases, or a compound stimulating the release of (NO) or a NO donor.
17. The drug delivery device or system of Claim 16, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative or the pharmaceutically acceptable salt of such a compound.
18. The drug delivery device or system of Claim 17, wherein fadrozole is a compound of formula (I)
HCI
19. The drug delivery device or system of Claim 18, wherein the compound of formula (I) is the (+) enantiomer.
20. The method of Claim 1 , or use of any of claims 2 to 5 and claim 11 , wherein the administration or delivery is intravascular, intranasal, intrabronchial, intraperitoneal or eosophagal.
21. The method of Claim 5 or use of any of claims 7 to 11 wherein the administration or delivery is intravascular, intranasal, intrabronchial, intraperitoneal or eosophagal.
22. A method for preventing or treating smooth muscle cell proliferation and migration in hollow tubes, or increased cell proliferation or decreased apoptosis or increased matrix deposition in a mammal in need thereof, comprising oral or local administration of a therapeutically effective amount of a pharmaceutical composition comprising an aldosterone synthase inhibitor in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a rapamycin derivative having mTOR inhibiting properties, a calcineurin inhibitor, an EDG receptor agonist, an anti-inflammatory agent, an anti-thrombotic, anti-platelet or anti-coagulant agent, an anti-proliferative agent, a microtubule stabilizing or destabilizing agent, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, a protein kinase C inhibitor, a statin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, an inhibitor of a modulator (i.e., antagonists or agonists) of kinases, and a compound stimulating the release of (NO) or a NO donor.
23. The method of Claim 22, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative.
24. A method for the treatment of intimal thickening in vessel walls comprising the controlled delivery from a catheter-based device or an intraluminal medical device of a therapeutically effective amount of a pharmaceutical composition comprising an aldosterone synthase inhibitor in conjunction with a therapeutic dosage of one or more other active ingredients, each being releasably affixed to the medical device and the other active ingredient being selected from a rapamycin derivative having mTOR inhibiting properties, a calcineurin inhibitor, an EDG receptor agonist, an anti-inflammatory agent, an anti-thrombotic, anti-platelet or anti-coagulant agent, an anti-proliferative agent, a microtubule stabilizing or destabilizing agent, a compound or antibody which inhibits the PDGF receptor tyrosine kinase or a compound which binds to PDGF or reduces expression of the PDGF receptor, a compound or antibody which inhibits the EGF receptor tyrosine kinase or a compound which binds to EGF or reduces expression of the EGF receptor, a compound or antibody which inhibits the VEGF receptor tyrosine kinase or a VEGF receptor or a compound which binds to VEGF, a protein kinase C inhibitor, a statin, a compound, protein, growth factor or compound stimulating growth factor production that will enhance endothelial regrowth of the luminal endothelium, a matrix metalloproteinase inhibitor, an inhibitor of a modulator (i.e., antagonists or agonists) of kinases, and a compound stimulating the release of (NO) or a NO donor.
25. The method of Claim 24, wherein the aldosterone synthase inhibitor is fadrozole or a fadrozole derivative.
26. The method of Claim 3 or the use of Claim 3, wherein the administration or delivery is made using a catheter delivery system, a local injection device, an indwelling device, a stent, a coated stent, a sleeve, a stent-graft, polymeric endoluminal paving or a controlled-release matrix.
27. The method of Claim 8 or the use of Claim 8, wherein the administration or delivery is made using a catheter delivery system, a local injection device, an indwelling device, a stent, a coated stent, a sleeve, a stent-graft, polymeric endoluminal paving or a controlled-release matrix.
28. The method of Claim 3 or the use of Claim 3, wherein fadrozole or a fadrozole derivative is administered from a stent or from a coating applied to a stent.
29. The method of Claim 8 or 13, the use of Claim 8 or 13, wherein fadrozole or a fadrozole derivative is administered from a stent or from a coating applied to a stent.
30. The method of Claim 3 or 12, the use of Claim 3 or 12, for the treatment or prevention of stenosis, restenosis or inflammation.
31. The method of Claims 22 or 23, for the treatment or prevention of stenosis, restenosis or inflammation.
32. The method of Claim 8 or use of Claim 8, for the treatment or prevention of stenosis, restenosis or inflammation.
33. The methods of Claims 24 or 25, for the treatment or prevention of stenosis, restenosis or inflammation.
34. The device of any of Claims 14 to 19, which is a catheter delivery system, a local injection device, an indwelling device, a stent, a stent-graft or a sleeve.
35. The device of any of Claims 14 to 19, which is a coated stent.
36. Use of a device of any of Claims 14 to 19 or 34 to 35, for the manufacture of a medicament for the prevention or reduction of vascular access dysfunction in association with the insertion or repair of an indwelling shunt, fistula or catheter into a vein or artery, in a subject in need thereof.
37. Use according to claim 36 for the prevention or reduction of stenosis, restenosis and/or hyperplasia, preferably in diabetic patients. The method or use of any of claims 30, 31 , 32, 33 or 36, the treatment or prevention of restenosis in diabetic patients.
PCT/EP2005/004117 2004-04-19 2005-04-18 Drug delivery systems for the prevention and treatment of vascular diseases WO2005099695A1 (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007088418A1 (en) * 2006-01-31 2007-08-09 Multi Gene Vascular Systems, Inc. Drug-eluting intravascular prostheses and methods of use
US7563278B2 (en) 2000-07-20 2009-07-21 Multi-Gene Vascular Systems Ltd. Drug-eluting intravascular prostheses and methods of use
US7887581B2 (en) 2000-07-20 2011-02-15 Multi-Gene Vascular Systems, Ltd. Methods of hemodialysis utilizing grafts coated with cells expressing human fibulin-5

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001076574A2 (en) * 2000-04-12 2001-10-18 Novartis Ag Novel medical use of aldosterone synthase inhibitors alone or in combination with at1-receptor antagonists
WO2002040007A1 (en) * 2000-11-17 2002-05-23 Novartis Ag Synergistic combinations comprising a renin inhibitor for cardiovascular diseases
US20030021787A1 (en) * 1999-01-26 2003-01-30 David Hung Method and devices for delivery of agents to breast milk ducts
US20030083342A1 (en) * 2002-08-27 2003-05-01 Steele Ronald Edward Combination of organic compounds
US20030162759A1 (en) * 2000-07-27 2003-08-28 Ricardo Rocha Aldosterone blocker therapy to prevent or treat inflammation-related disorders
WO2003099279A1 (en) * 2002-05-29 2003-12-04 Novartis Ag Combination of a dpp iv inhibitor and a cardiovascular compound

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030021787A1 (en) * 1999-01-26 2003-01-30 David Hung Method and devices for delivery of agents to breast milk ducts
WO2001076574A2 (en) * 2000-04-12 2001-10-18 Novartis Ag Novel medical use of aldosterone synthase inhibitors alone or in combination with at1-receptor antagonists
US20030162759A1 (en) * 2000-07-27 2003-08-28 Ricardo Rocha Aldosterone blocker therapy to prevent or treat inflammation-related disorders
WO2002040007A1 (en) * 2000-11-17 2002-05-23 Novartis Ag Synergistic combinations comprising a renin inhibitor for cardiovascular diseases
WO2003099279A1 (en) * 2002-05-29 2003-12-04 Novartis Ag Combination of a dpp iv inhibitor and a cardiovascular compound
US20030083342A1 (en) * 2002-08-27 2003-05-01 Steele Ronald Edward Combination of organic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
HAYASHI T ET AL: "Dehydroepiandrosterone retards atherosclerosis formation through its conversion to estrogen: The possible role of nitric oxide", ARTERIOSCLEROSIS, THROMBOSIS, AND VASCULAR BIOLOGY 2000 UNITED STATES, vol. 20, no. 3, 2000, pages 782 - 792, XP002338850, ISSN: 1079-5642 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7563278B2 (en) 2000-07-20 2009-07-21 Multi-Gene Vascular Systems Ltd. Drug-eluting intravascular prostheses and methods of use
US7887581B2 (en) 2000-07-20 2011-02-15 Multi-Gene Vascular Systems, Ltd. Methods of hemodialysis utilizing grafts coated with cells expressing human fibulin-5
US8022195B2 (en) 2000-07-20 2011-09-20 Multi-Gene Vascular Systems, Ltd. Vectors encoding cell growth and adhesion factors for simultaneous growth and adhesion of cells
US8088160B2 (en) 2000-07-20 2012-01-03 Multi-Gene Vascular Systems Ltd. (“MGVS”) Drug-eluting intravascular prostheses and methods of use
WO2007088418A1 (en) * 2006-01-31 2007-08-09 Multi Gene Vascular Systems, Inc. Drug-eluting intravascular prostheses and methods of use

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