WO2006019204A1 - Composition pharmaceutique contenant de la thalidomide pour traiter et pour prevenir une restenose arterielle - Google Patents

Composition pharmaceutique contenant de la thalidomide pour traiter et pour prevenir une restenose arterielle Download PDF

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Publication number
WO2006019204A1
WO2006019204A1 PCT/KR2004/002321 KR2004002321W WO2006019204A1 WO 2006019204 A1 WO2006019204 A1 WO 2006019204A1 KR 2004002321 W KR2004002321 W KR 2004002321W WO 2006019204 A1 WO2006019204 A1 WO 2006019204A1
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Prior art keywords
thalidomide
tnf
neointimal
bfgf
injury
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PCT/KR2004/002321
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English (en)
Inventor
Hyo-Soo Kim
Bon-Kwon Koo
Hyun-Jae Kang
Seung-Jung Park
Byung-Doo Kwon
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Seoul National University Industry Foundation
Stentech.Inc.
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Publication of WO2006019204A1 publication Critical patent/WO2006019204A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • This present invention relates to pharmaceutical compositions for the treatment and prevention of all sorts of vascular stenosis, restenosis and atherosclerosis in all circulatory systems, specifically by systemic or local administration of thalidomide alone or in combination with other agents which have a inhibitory effect on neointimal hyperplasia.
  • vascular smooth muscle cells VSMCs
  • leukocytes vascular smooth muscle cells
  • Serrano CV Jr Ramires JA, Venturinelli M, Arie S, D'Amico E, Zweier JL, Pileggi F, da Luz PL., J Am Coll Cardiol 1997; 29: 1276-83 .
  • Activated VSMCs and leukocytes are known to release various types of cytokines and growth factors (Clausell N, de Lima VC, Molossi S, Liu P, Turley E, Gotsch AI, Adelman AG, Rabinovitch M. r Br Heart J 1995;73:534-9, Lowe HC, Chesterman CN, Hopkins AP, Juergens CP, Khachigian LM.
  • thalidomide has since been shown to have potent anti-inflammatory and immunomodulatory properties (Raje N, Anderson K., N Engl J Med 1999; 341:1606-9) .
  • thalidomide a wide spectrum of diseases including cutaneous lupus, Crohn's disease, rheumatoid arthritis, multiple myeloma and Graft versus host disease, are being treated with thalidomide (Raje N, Anderson K. * , N Engl J Med 1999; 341:1606-9) .
  • TNF tumor necrosis factor
  • thalidomide was recently administered to patients with chronic symptomatic congestive heart failure, who showed reduced TNF- ⁇ level and increased left ventricular ejection fraction after 6 months of thalidomide therapy(Gullestad L, Semb AG, Holt E, Skardal R, Ueland T, ⁇ ndestad A, Froland SS, Aukrust P., Am Heart J 2002/144:847-50) .
  • cytokine that may be attenuatedby thalidomide is bFGF, a pleotrophic molecule, (Raje N, Anderson K., N Engl J Med 1999; 341:1606-9) whose mRNA is overexpressed in cytoplasms and nuclei of proliferating VSMCs and endothelial cells following balloon injury (Lindner V, ReidyMA., Circ Res 1993; 73:589-95) .
  • bFGF a pleotrophic molecule
  • Thalidomide specifically binds to these GC promoter sites because it has a greater affinity for guanine, which is due to the fact that the structure of guanine more resemble thalidomide than that of adenine (Jonsson NA., Acta Pharm Suec 1972; 9:543-62) .
  • the molecules that are regulated by GC boxes instead of TATA or CCAAT boxes include manyproteins such as Insulin-like growth factor (IGF) -1, IGF-I receptor, bFGF rececptor and ⁇ v ⁇ 3 integrin.
  • IGF Insulin-like growth factor
  • thalidomide has been reported to reduce the synthesis of other pro-inflammatory cytokines such as IL-I, IL-6 and IL-8 (Raje N, Anderson K., N Engl J Med 1999;341 :1606-9, Finnell RH, Waes JG, Eudy JD, Rosenquist TH., Annu Rev Pharmacol Toxicol 2002/42:181-208) , but it enhances levels of the anti-inflammatory cytokine IL-10 (Gullestad L, Semb AG, Holt E, Skardal R, Ueland T, ⁇ ndestad A, Froland SS, Aukrust P., Am Heart J 2002;144:847-50) .
  • Thalidomide was also found to reduce the expression of endothelial adhesion molecules including integrin, ICAM and VCAM, (Raje N, Anderson K., N Engl J Med 1999; 341:1606-9, Settles B, Stevenson A, Wilson K, Mack C, Ezell T, Davis MF, Taylor LD., Cell MoI Biol 2001; 47:1105-14) as a consequence, the interactions between endothelial cells and circulating leukocytes are inhibited.
  • NF- ⁇ B an important mediator of inflammation, cell proliferation and restenosis
  • I- ⁇ B degradation was also found to be blocked with thalidomide due to its inhibitory effect upon I- ⁇ B degradation (Bergmeister H, Kadi A, Baumgartl G, Steurer S, Xu Z, Koshelnick Y, Lipp J, de Martin R, Losert U, Lammer J, Binder BR. , Circulation 2002/105: 633-8, Majumdar S, Lamothe B, Aggarwal BB., J Immunol 2002/168:2644-51, Breuss JM, Cejna M) .
  • thalidomide has never been reported to exert a significant inhibitory effect on neointimal growth through either animal experiments or clinical trials.
  • thalidomide As an anti-restenotic agent for the treatment and prevention of arterial stenosis, the present invention was completed.
  • the present invention provides a method and compositions to treat and prevent vascular stenosis after revascularization.
  • a pharmaceutical composition of the present invention for the treatment and prevention of vascular stenosis is characterized by- containing thalidomide as an active ingredient.
  • Thalidomide originally synthesized as a sedative, has since been shown to have potent anti-inflammatory, anti-angiogenic and immunomodulatory properties. Presently, the use of it has expanded to various clinical areas where inflammation is thought to play an important role, such as refractory cutaneous lupus, rheumatoid arthritis, Crohn's disease, multiple myeloma and chronic graft versus host disease.
  • thalidomide has been proved to show less toxicity in animal experiments even at 10g/kg.
  • a pharmaceutical composition of the present invention for the treatment and prevention of vascular stenosis, inhibiting significantly neointimal hyperplasia due to its anti-inflammatory effect and its anti-proliferative action, can be applied as a useful anti-restenotic agent for the treatment and prevention of vascular stenosis.
  • Figures 1 show low andhighmagnificationphotomicrographs of arterial section from the control and fromthalidomide-treated groups (NI: Neointima, M: Media, Ad: Adventitia) .
  • E Carotid artery of control group 2 weeks after procedure
  • F Carotid artery of thalidomide group 2 weeks after procedure
  • G Carotid artery of control group 2 weeks after procedure
  • H Carotid artery of thalidomide group 2 weeks after procedure (A-F: low magnigication, G and H: high magnification)
  • Figures 2a are the histomorphometric data showing luminal, neointimal and medial area collected from both control and thalidomide group 2 weeks
  • Figures 2b are the graphs representing neointimal area to medial area
  • Figures 4a and 4b are the results of western blot anaylsis used to ascertain the effect of thalidomide treatment on the local expressions of
  • TNF- ⁇ and bFGF respectively in an injured vessel.
  • Figures 5 represent effect of thalidomide treatment on the local expression of bFGF in an injured vessel using immunohistocherciical analysis.
  • Figures 6 are the graphs of bFGF positive indices in control and thalidomide-treated groups (*: p ⁇ 0.001) .
  • Figures 7 are the immunohistochemical analysis of infiltration of macrophages in carotid arteries using ED-I staining (NI: Neointima, M:
  • Figures 9 are the immunohistochemical analysis of carotid arteries used to determine the proliferation of VSMCs in control and thalidomide-treated groups (NI: Neointima, M: Media, i: PCNA positive cell) .
  • a model of de-novo neointimal growth in response to vascular injury is used to confirm whether thalidomide has a suppressive effect on neointimal proliferation.
  • neointimal growth was significantly inhibited in the thalidomide-treated groups, which resulted in larger luminal area in that groups compared with control groups.
  • serum TNF- ⁇ was measured by ELISA to investigate the effects of thalidomide on TNF- ⁇ production.
  • TNF- ⁇ as a central mediator of inflammatory response, is known to be expressed by activatedmacrophages or VSMCs after balloon angioplasty.
  • thalidomide significantly decreased serum TNF- ⁇ , which is a marker of systemic inflammation, after balloon injury.
  • Figure 3b shows a strong positive correlation between the serum TNF- ⁇ level and the degree of neointimal growth. Therefore, the lower the serum TNF- ⁇ level, the smaller the N/M ratio. The lower the level of inflammation, the lower development of neointimal hyperplasia is.
  • thalidomide treatment suppressed not only the systemic release of TNF- ⁇ but also its local expression in injured arteries, which suggest that thalidomide therapy inhibits the development of neointimal overgrowth via its inhibitory effect on systemic and local inflammatory response to vascular injury. Therefore, thalidomide administration induced the suppressed macrophage infiltration and the reduced expression of TNF- ⁇ and bFGF, which led to the decreased proliferative activity of VSMCs and then to the attenuated neointimal hyperplasia.
  • Thalidomide described above can be directly synthesized by anymethod known in the art. Certain of this compound such as ThalidomidTM and SauramideTM, are commercially available for use. In a specific embodiment of the present invention, thalidomide purchased from Alan Pharmaceuticals (SauramideTM) was employed. Therapeutic dose of the compound of the present invention can be determined variably according to the kind of target vessel, general condition of the individual patient and the duration of treatment as previously designed. For example, daily practical doses of the compound can vary to obtain a plasma concentration of 2.0ug/mL or more. In a specific embodiment of the present invention, administration of thalidomide at 100mg/kg/day for 2 weeks, can achieve a significant suppression of the neointimal hyperplasia.
  • the compounds of the present invention are highly effective for the treatment and prevention of vascular restenosis.
  • the arterial stenosis mentioned above may be due to neointimal hyperplasia.
  • This stenosis may also be induced by percutaneous transluminal coronary angioplasty, atherectomy, stent implantation, coronary artery bypass grafting and arteriovenous • anatomosis.
  • compositions from the compounds of the present invention many pharmaceutically acceptable carriers may be employed.
  • Pharmaceutically acceptable carriers encompass but are not limited to normal saline, buffered normal saline, sterile water, glycerol, ethanol, etc.
  • the compositions described above may contain pharmacologically acceptable auxiliary substances as required, such as excipient, stabilizer, dispersing agent, lubricating agent, preserving agent, suspending agent, sweetening agent, flavoring agent and binder.
  • composition can be prepared in the form of tablets, pills, capsules, granules, powders, elixirs, suspensions, emulsions, syrups, solutions, oils, ointments, creams.
  • Routes of administration ⁇ of the present invention include oral and parenteral route.
  • the compounds of the present invention can be coated alone or in combination with other agent, on a stent or a synthetic vascular graft, which may be coated by preferable methods known in the art, such as dip coating and polymer-based coating.
  • the optimal dose to be administered will vary in consideration of other associated conditions.
  • the daily dose range of the compound administered orally is between lOOmg to 1600mg.
  • the dose of the compounds can be adjusted reasonably according to the age, sex, body weight, general condition of patient, diet, administration route and interval, absorption rate, bioavailability, the severity of disease, other drugs in use, etc.
  • Thalidomide (SauramideTM, Alan Pharmaceutical, London, U.K.) was dissolved in corn oil (Sigma-Aldrich Korea) to give a 50mg/ml suspension.
  • thalidomide 100mg/kg qd was administered to the rats in the study by gavage from 3days prior to balloon injury.
  • balloon injury was performed as follows; under Xylazine (5 mg/kg IP; Yuhan Corp, Bayer Korea) and ketamine hydrochloride (50 mg/kg IP; Yuhan Corp, Bayer Korea) induced anesthesia, the right external carotid arteries were exposed and the common carotid arteries were denuded of endothelium by the intraluminal passage of a 2F arterial catheter (Baxter Healthcare Corp) , which was passed to the proximal common carotid artery and withdrawn in the, inflated state 5 times .
  • Xylazine 5 mg/kg IP; Yuhan Corp, Bayer Korea
  • ketamine hydrochloride 50 mg/kg IP; Yuhan Corp, Bayer Korea
  • thalidomide of the same dose 100 mg/kg qd was administered by gavage to the rats that underwent the vascular injury for 2 weeks.
  • Control animals were given 100mg/kg of sucrose in the same manner.
  • Bilateral common carotid arterial segments about lcm long,were harvested and perfusion fixed with 10% neutral buffered formalin at physiological pressure. Tissues were then embedded in paraffin, and 4 to 6 sections 4 ⁇ m thick were cut from 4 equally spaced locations from the harvested arterial segments. The sections were stained with hematoxylin and eosin or Verhoeff-van Gieson stain. The luminal, neointimal, and medial areas were calculated using the Image-Pro Plus 4.5 software (Media Cybernetics Inc.) .
  • Figure 1 shows low and high magnification photomicrographs of arterial section from the control and thalidomide-treated groups before and after the procedure (NI: Neointima, M; Media, Ad: adventitia) .
  • NI Neointima, M
  • Media, Ad Adventitia
  • Morphometric analysis 3 days after balloon injury revealed no significant differences in the neointimal or medial areas of the thalidomide-treated and control groups (C, D, n 8 per group) . No neointima could be found in either group.
  • Figure 2a is the histomorphometric data showing luminal, neointimal and medial area collected from both control and thalidomide group 2 weeks after balloon injury.
  • Figure 2b is the graphs representing neointimal area to medial area (N/M) ratio of control and thalidomide groups 2 weeks after balloon injury. In the thalidomide-treated animals, there was a 71%
  • Example 2 Determination of anti-inflammatory effect To understand the mechanism of thalidomide treatment in vivo, inflammatory and proliferative activities of the injured carotid arteries were examined. Injured vessel segments and arterial blood were collected at 3days and 14 days after the injury for the following measurements.
  • TNF- ⁇ as a central mediator of inflammation,is known to be expressed by activated leukocytes and VSMCs in injured arteries after balloon angioplasty(Tanaka H, Sukarva G, Schwartz D, Libby P., Arterioscler Thromb Vase Biol 1996 / 16:12-8, Clausell N, de Lima VC, Molossi S, Liu P, TurleyE, GotschAI, AdelmanAG, Rabinovitch M. , Br Heart J 1995;73:534-9) .
  • neointimal VSMCs were demonstrated to express TNF- ⁇ along with its iriRNA and to sustain proliferation even IOdays after injury(Tanaka H, Sukhova G, Schwartz D, Libby P., Arterioscler Thromb Vase Biol 1996/16:12-8) , and the local blockade of TNF- ⁇ with TNF- ⁇ antibody eluting stentreduced VSMC proliferation in saphenous vein organ culture (Javed Q, SwansonN, Vohra H, ThurstonH, GershlickAH. , ExpMoI Pathol 2002/73:104-11) .
  • tissue macrophage infiltration in the neointima andmedia which is a major sources of TNF- ⁇ , was ,shown to be significantly increased and sustained till 2 to 4 weeks after injury (Mori E, Komori K, Yamaoka T, Tanii M, Kataoka C, Takeshita A, Usui M, Egashira K, Sugimachi K., Circulation 2002/105: 2905-10, Bishop GG, McPherson JA, Sanders JM, Hesselbacher SE, Feldman MJ, McNamara CA, Gimple LW, Powers ER, Mousa SA, Sarembock IJ., Circulation 2001 / 103:1906-11) .
  • serum TNF- ⁇ was measured as follows on days3 and 14 after the balloon injury.
  • TNF- ⁇ level was measured in duplicate with a commercial enzyme-linked immunosorbent assay (ELISA) kit purchased from BD PharMingen (CA, USA) .
  • ELISA enzyme-linked immunosorbent assay
  • thalidomide significantly decreased serum TNF- ⁇ , which is a marker of systemic inflammation, by 48% and 51% on 3 and 14 days after balloon injury respectively, (control" versus thalidomide 856
  • Vessel tissues were homogenized in lysis buffer and protein concentrations were determined using a Micro BCA Protein Assay kit (Pierce) . Twenty micrograms of protein per specimen were separated on a SDS-polyacrylamide gel, blotted onto nitrocellulose membranes, and probed
  • Macrophage recruitment and infiltration occurs at sites of vascular injury, which is a major source of various cytokines and growth factor (Danenberg HD, Welt FG, Walker M 3rd, Seifert P, Toegel GS, Edelman ER., Circulation 2002;105:2917-22, Bishop GG, McPherson JA, Sanders JM, Hesselbacher SE, Feldman MJ, McNamara CA, Gimple LW, Powers ER, Mousa SA, Sarembock IJ., Circulation 2001;103:1906-11) .
  • Species-specific antibodies were used to immunohistochemically identifymacrophages infiltration (ED-I, Serotec) and bFGF expression (Santa Cruz Biotechnology) .
  • TNF- ⁇ and bFGF in the injured vessels was confirmed by western blot analysis
  • Figures 6 are the graphs of bFGF-positive indices in control and thalidomide-treated groups.
  • the indeces were measure by counting bFGF-positive nuclei against the total nuclei in the neointimal and medial smooth muscle cells.
  • Figure 1 is the immunohistochemical staining of the glycoprotein ED-I (HOkD) expressed predominantly on the lysosomal membrane of tissue macrophages, which cells are major sources of TNF- ⁇ andmany other cytokine. Brown cytoplasmic stain indicates ED-I positive tissue macrophages.
  • HkD glycoprotein ED-I
  • Macrophage recruitment and infiltration into the injured arteries of thalidomide-treated animals was dramatically reduced (C) versus the control group (B) two weeks after balloon injury. Specifically, the number of recruited macrophages was decreased by 79 % ( Figure 8, control versus
  • Example 3 Determination of anti-proliferative activity
  • PCNA proliferating cell nuclear antigen
  • Figure 9 is the immunohistochemical analysis of the proliferation of VSMCs of rat carotid arteries in control and thalidomide-treated animals before and after the angioplasty, which figure showed that suppressed inflammation was accompanied by a reduction in the proliferative activity of VSMCs.
  • a remarkable fall-off in the number of PCNA-positive VSMCs was demonstrated in the medial layers of arteries of thalidomide-treated rats 3 days after injury (D) .
  • this anti-proliferative effect of thalidomide was sustained till 14 days after the injuries in the neointimal and medial layers of thalidomide-treated animals (F) .
  • the arrows indicate typical PCNA-positive cells.
  • PCNA-positive cells in the media and neointima were counted and are presented as mean ⁇ SD.

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Abstract

L'invention concerne des compositions pharmaceutiques contenant de la thalidomide pour traiter et pour prévenir une sténose artérielle. L'invention concerne des compositions pharmaceutiques pour traiter et pour prévenir une sténose vasculaire, pour inhiber sensiblement une hyperplasie néointime, grâce aux effets anti-inflammatoires et à l'action antiproliférative de la thalidomide. Ces compositions peuvent être appliquées pour servir d'agents anti-resténose utiles pour traiter et pour prévenir une sténose vasculaire.
PCT/KR2004/002321 2004-08-16 2004-09-14 Composition pharmaceutique contenant de la thalidomide pour traiter et pour prevenir une restenose arterielle WO2006019204A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020054899A1 (en) * 1999-12-15 2002-05-09 Zeldis Jerome B. Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020054899A1 (en) * 1999-12-15 2002-05-09 Zeldis Jerome B. Methods and compositions for the prevention and treatment of atherosclerosis, restenosis and related disorders

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
GELATI ET AL: "Effects of thalodomide on parameters involved in angiogenesis an in vitro study", J NEUROONCOL, vol. 64, no. 3, September 2003 (2003-09-01), pages 193 - 201 *
GUPTA ET AL: "Adherence of multiple myeloma cells to bone marrow stromal cells upregulates vascular endothelial growth factor secretion: therapeutic applications.", LEUKEMIA, vol. 15, no. 12, December 2001 (2001-12-01), pages 1950 - 1961 *
LI ET AL: "Thalidomide down-regulates the expression of VEGF and bFGF in cisplatin-resistant human lung carcinoma cells.", ANTICANCER RES, vol. 23, no. 3, March 2003 (2003-03-01), pages 2481 - 2487 *
MCCARTY: "Thalidomide may impede cell migration in primates by down-regulating integrin beta-chains: potential therapeutic utility in solid malignancies, proliferative retinopathy, inflammatory disorders, neointimal hyperplasia, and osteoporosis.", MED HYPOTHESES, vol. 49, no. 2, August 1997 (1997-08-01), pages 123 - 131, XP001084335, DOI: doi:10.1016/S0306-9877(97)90217-6 *
MOREIRA ET AL: "Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation invitro.", J NEUROONCOL, vol. 43, no. 2, June 1999 (1999-06-01), pages 109 - 114, XP001084333, DOI: doi:10.1023/A:1006202700039 *
PARK ET AL: "Thalidomide as a potent inhibitor of neointimal hyperplasia after balloon injuryin rat carotid artery.", ARTERIOSCLER THROMB VASC BIOL, vol. 24, no. 5, May 2004 (2004-05-01), pages 885 - 891 *

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