US20110105961A1 - Methods, compositions and apparatuses for facilitating regeneration - Google Patents

Methods, compositions and apparatuses for facilitating regeneration Download PDF

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US20110105961A1
US20110105961A1 US12/994,421 US99442109A US2011105961A1 US 20110105961 A1 US20110105961 A1 US 20110105961A1 US 99442109 A US99442109 A US 99442109A US 2011105961 A1 US2011105961 A1 US 2011105961A1
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cells
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Lewis S. Gruber
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Siwa Corp
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Siwa Corp
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
    • A61K47/6817—Toxins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6843—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5091—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing the pathological state of an organism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/1815—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using microwaves
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/18—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves
    • A61B18/20—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by applying electromagnetic radiation, e.g. microwaves using laser
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00452—Skin
    • A61B2018/0047—Upper parts of the skin, e.g. skin peeling or treatment of wrinkles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A61N7/02—Localised ultrasound hyperthermia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/73—Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation

Definitions

  • the present invention relates in general to methods, compositions and apparatus for promoting tissue and organ regeneration, and in particular to preventing cells from inhibiting regenerative processes to obtain the recognized benefits in health and function associated with the results of regeneration.
  • Tissue and organ regeneration research has focused on the need to stimulate regeneration by activating stem cells by soluble factors or treat partially- or non-functional cells to improve their function, e.g. by breaking damage-related crosslinks. Such research has overlooked the need to remove inhibitory effects.
  • the present invention provides apparatus, compositions and methods for removing cells that interfere with regenerative processes by blocking locations in a tissue where progeny of stem cells can improve function.
  • the present invention also reduces the proportion of partially- and non-functional cells without regard to location in a tissue.
  • Functionality according to the present invention is defined as the state of operation of a cell of the same type in a selected healthy individual.
  • the apparatuses, compositions and methods according to the present invention promote regenerative processes by differentially killing cells based inversely on the degree of functionality of the cells (i.e., the less functionality the more likely to be killed), and then applying that technique.
  • This cell killing technique preferentially preserves proliferating cells.
  • any of lipofuscin, glycation end-products or cell stiffness can be selected as a proliferation-preserving marker of partial- or non-functionality.
  • Cell killing technologies directed against such markers can include, respectively, lasers/intense light, antibodies, and ultrasound.
  • Cells can be killed according to the present invention by physical, electromagnetic, chemical or biological techniques, for example. Physical techniques include without limitation ultrasound and other oscillatory methods for disrupting cell membranes or structures leading to cell death.
  • Electromagnetic techniques include without limitation and as targeted by sensitizers (such as absorbent nanoparticles, for example) EMF (see, e.g., Litovitz, U.S. Pat. No. 7,367,988 for EMF methods), high intensity light, radio waves microwaves, lasers, magnetism and ionizing radiation.
  • Chemical techniques include without limitation toxic nanoparticles, chemical toxins and structure removal compounds such as ⁇ -aminopropionitrile.
  • Biological techniques include without limitation antibodies against partially-functional or non-functional cells and variations and modifications thereof, such as toxin conjugates and natural killer cells modified to express target-specific antibodies. Techniques can be combined as determined to be effective (e.g. see McHale et al., U.S. Pat. No. 6,821,274 for sensitization to ultrasound by EMF treatment). Apparatuses, methods and compositions according to the present invention can be used sequentially or simultaneously in combination as monitoring determines to be effective for promoting regeneration.
  • the apparatuses, compositions and methods selectively kill partially and/or non-functional cells versus functional cells of the same cell type to the extent that, upon removal of the killed cells by disintegration or scavenging, functional cells replace them.
  • the cell killing apparatus, compositions and methods according to the present invention must preferentially preserve proliferating, functional cells and must be of a degree that avoids excessive inflammatory responses.
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the apparatus, compositions and methods according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
  • the FIGURE illustrates apparatus according to the present invention.
  • Proliferating cells include both cells that are dividing and cells, such as stem cells, that divide normally when stimulated to do so.
  • stem cells participate in mundane tissue replacement, injury can also be an occasion for release of a factor or factors to stimulate stem cell proliferation and differentiation.
  • Stem cells give rise to cells which heal the injury, for example, healing a cut in an epithelium.
  • stem cell division and differentiation would be abnormal, even tumorigenic, in the presence of a normal complement of cells. Accordingly, there are mechanisms to prevent excessive proliferation. For example, the presence of a cell at a location in an epithelium prevents replacement at that position.
  • An example of this sort of phenomenon is contact inhibition where cells cease proliferating when they come in contact with other cells.
  • the phenomenon can be generalized to a rule that, to facilitate stem cell proliferation and differentiation for regeneration of cells at a location, there can not be a cell or structure at the location in the tissue.
  • the human body includes cells for tearing down a structure, such as osteoclasts in bone, as well as cells for building up a structure, such as osteoblasts in bone. It is the balance between the activities of the two types of cells that determines the extent of the resulting structure. To the extent that any intrinsic mechanisms do not remove cells/structure for periodic renewal, the present invention provides for removal to promote regeneration.
  • the cell at the location that inhibits stem cell action can be fully functional, partially functional, or non-functional.
  • Dead cells can be removed by scavenging macrophages, thus allowing for replacement, but a malfunctioning cell may remain despite deleterious effects on the subject (i.e., the organism of which they are a part).
  • a partially or non-functional cell i.e. a malfunctioning cell, can not be apoptotic, and, thus, can not stimulate clearance by macrophages on its own.
  • Such malfunctioning cells are killed according to the present invention for removal by the body's natural processes.
  • Therapeutic killing of cells in cancer therapy is targeted against proliferating cells, the exact opposite of the present invention.
  • action against cancer is provided by stimulating proliferation of stem cells so that error-correcting mechanisms that function during cell division can correct mutations that otherwise might accumulate in a non-dividing cell.
  • partially or non-functional cells according to the present invention can fail to be fully functional due to damage, such as free radical damage, or cross-linkage as a result of reaction with sugars, i.e. glycation.
  • Damage such as free radical damage, or cross-linkage as a result of reaction with sugars, i.e. glycation.
  • Cells that are partially or non-functional due to a genetic makeup that is shared by stem cells of a subject can be replaced by exogenous stem cells having a fully functional genetic makeup.
  • Non-cellular material such as scar tissue, can block such regeneration. This can explain failures in regeneration and in stem cell transplantation.
  • non-cellular blocking structures can be removed according to the present invention.
  • regenerative cells such as stem cells
  • transplantation With removal of blocking cellular and/or non-cellular materials, appropriate regenerative cells, such as stem cells, are retained or supplemented by transplantation in order to permit regeneration.
  • “Fully functional” is defined as the degree of a specified function for a particular cell type exhibited by an available progeny of a stem cell in a subject with or without stem cell transplantation, whichever is greater.
  • Effector 10 is a device for killing cells. Effector 10 can be, without limitation, ultrasound equipment or a device for antibody administration, such as a drip apparatus.
  • Control 20 is a device for regulating the operation of effector 10 according to preset parameters and/or as modified to ensure safety or effectiveness. Without limitation, control 20 can be a control panel of effector 10 .
  • Monitor 30 provides information regarding the degree of inflammatory response and/or other important factors in the condition of the subject to which effector 10 is applied. Information from monitor 30 can be used to adjust control 20 and thereby to adjust or change the operation of effector 10 . Monitor 30 can be, without limitation, a thermometer connected to control 20 .
  • a technique according to the present invention is selected to preferentially kill partially functional or nonfunctional cells or to remove non-cellular compositions, as opposed to indiscriminate killing, which has as great an effect on functional cells.
  • a technique may be selected according to the present invention by exposing functional and partially functional and/or non-functional cells to the technique and choosing concentrations, intensities and characteristics such as wavelength, frequency, wave shape, continuity and treatment duration.
  • concentrations, intensities and characteristics such as wavelength, frequency, wave shape, continuity and treatment duration.
  • the technique to be applied to a particular subject can be chosen on the basis of identifying an acceptable selectivity for partially functional and/or non-functional cells versus functional cells.
  • selection methods and criteria are readily available to those skilled in the art. Such selection methods are routinely applied by those of skill in the relevant arts to select laser treatment levels for removing blemishes, treating cancers by radiation therapy, selecting monoclonal antibodies, selecting toxins to be used therapeutically, and selecting ultrasound properties for therapy, for example. According to the present invention, selected techniques discriminate functional versus non-functional and/or partially functional cells of the same cell type as the functional cells.
  • Techniques that act upon differences between functional and partially or non-functional cells can be based upon cellular properties associated with dysfunction, such as cross-linking, membrane stiffness and brown coloration associated with lipofuscin in aged or senescent cells as opposed to nascent, dividing or functional cells.
  • Techniques such as ultrasound, targeted to harmonic frequencies of cross-linked cell membranes or components, can be used according to the present invention.
  • techniques such as lasers or intense light of a wavelength preferentially absorbed by partially functional or non-functional cells can be used according to the present invention.
  • Techniques according to the present invention can be used to localize therapy where needed. Localization can be accomplished by, without limitation, computer assisted tomography, magnetic resonance imaging, and positron emission tomography. Most preferably, techniques according to the present invention can be applied to the whole organism without the need for localization.
  • the techniques can be applied periodically, particularly at a low intensity or concentration, to maintain or increase a positive balance between functional versus partially or non-functional cells. Gradual versus precipitate cell killing can aid in avoiding toxic effects from high levels of cellular breakdown products and/or deleterious effects of an inflammatory response.
  • non-therapeutic, non-human and industrial applications be included within the scope of the present invention.
  • Cosmetic applications, diagnostic applications and veterinary applications are also contemplated.
  • Repeatedly practicing the method according to the present invention at a low level can be coupled with monitoring to determine the degree of improvement as a diagnostic measure of the component of a condition due to damaged cells versus genetic factors.
  • destruction of blocking cells can permit the resulting dead cells and debris to be washed away. In this way, productivity of cell and tissue cultures can be increased by increasing the relative proportion of productive cells versus non-productive cells.
  • glycation end-products crosslinks created by sugars bonded to proteins, are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality.
  • Antibodies against such glycation end-products can be raised according to methods well known to those skilled in the art (e.g. Abed et al., U.S. Pat. No. 6,380,165; Bucala, U.S. Pat. No. 5,702,704) and humanized monoclonal antibodies retaining constant regions which permit destruction of targeted cells by the immune system can be produced for injection, also according to well known methods (e.g. Basi et al., U.S. Pat. No. 7,256,273).
  • Antibodies can be screened for effectiveness according to the present invention by labeling them and applying them separately to untreated cells versus cells incubated with a sugar such as ribose used to induce formation of glycation end-products. Binding of the antibodies to a higher degree to the cells previously incubated with sugar as opposed to the cells not treated with sugar indicates preferential effect against the selected target.
  • a sugar such as ribose used to induce formation of glycation end-products.
  • Antibodies produced as described above can be administered to a subject intravenously with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of the antibodies according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.
  • glycation end-products are selected as indicia of an accumulation of cellular damage correlated with partial- or non-functionality. This crosslinking manifests itself in a stiffening of the cells. Those in the art understand stiffness to distinguish types of proliferating versus non-proliferating cells (e.g. Kas et al., U.S. Pat. No. 6,067,859).
  • Ultrasound apparatus can be used according to practices well known to those skilled in the art to destroy cells by vibrational techniques (e.g. Chapelon et al., U.S. Pat. No. 5,601,526).
  • Ultrasound parameters e.g. frequency, power, and pulsation
  • Vibrational versus thermal destruction by ultrasound is preferred according to the present invention. Parameters selected for preferential destruction of sugar-treated cells as opposed to the cells not previously treated with sugar indicates preferential effect against the selected target.
  • Ultrasound as described above can be applied to a subject with monitoring to determine that inflammatory responses such as fever or swelling do not exceed limits well known to be safe. This process can be repeated at intervals to maintain a level of regeneration. The process can be focused to remove partially- and/or non-functional cells a particular location (e.g. where stem cell transplantation is targeted).
  • Evaluation of improvement or maintenance of a desired result can be used to direct the frequency of reapplication of ultrasound according to the present invention.
  • the application and reapplication can be determined with the goal of gradual improvement to avoid overwhelming natural mechanisms, such as removal of cells/debris by scavenging cells.

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US12/994,421 2008-05-23 2009-05-22 Methods, compositions and apparatuses for facilitating regeneration Abandoned US20110105961A1 (en)

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US5584608P 2008-05-23 2008-05-23
US12/994,421 US20110105961A1 (en) 2008-05-23 2009-05-22 Methods, compositions and apparatuses for facilitating regeneration
PCT/US2009/044951 WO2009143411A2 (en) 2008-05-23 2009-05-22 Methods, compositions and apparatus for facilitating regeneration

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US13/332,976 Continuation US9161810B2 (en) 2008-05-23 2011-12-21 Methods, compositions and apparatuses for facilitating regeneration
US14/932,200 Continuation US20180111982A2 (en) 2008-05-23 2015-11-04 Methods, compositions and apparatuses for facilitating regeneration

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US13/332,976 Active 2031-08-17 US9161810B2 (en) 2008-05-23 2011-12-21 Methods, compositions and apparatuses for facilitating regeneration
US14/932,200 Abandoned US20180111982A2 (en) 2008-05-23 2015-11-04 Methods, compositions and apparatuses for facilitating regeneration
US15/720,912 Active US11261241B2 (en) 2008-05-23 2017-09-29 Methods, compositions and apparatuses for facilitating regeneration

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US15/720,912 Active US11261241B2 (en) 2008-05-23 2017-09-29 Methods, compositions and apparatuses for facilitating regeneration

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US (4) US20110105961A1 (es)
EP (3) EP2294178B1 (es)
JP (6) JP2011521009A (es)
KR (4) KR20110000585A (es)
CN (2) CN102037119B (es)
AU (1) AU2009248945B2 (es)
BR (1) BRPI0913047A2 (es)
CA (1) CA2724886C (es)
DK (1) DK2789684T3 (es)
ES (2) ES2499395T3 (es)
HK (2) HK1150628A1 (es)
HU (1) HUE031902T2 (es)
IL (3) IL209513A (es)
MX (2) MX342994B (es)
PL (1) PL2789684T3 (es)
PT (1) PT2789684T (es)
RU (2) RU2553225C2 (es)
WO (1) WO2009143411A2 (es)
ZA (1) ZA201008209B (es)

Cited By (16)

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