WO1995009612A1 - Substances encapsulees et non encapsulees pouvant liberer de l'oxyde nitrique et utilisees comme agents antimicrobiens - Google Patents

Substances encapsulees et non encapsulees pouvant liberer de l'oxyde nitrique et utilisees comme agents antimicrobiens Download PDF

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WO1995009612A1
WO1995009612A1 PCT/US1994/011441 US9411441W WO9509612A1 WO 1995009612 A1 WO1995009612 A1 WO 1995009612A1 US 9411441 W US9411441 W US 9411441W WO 9509612 A1 WO9509612 A1 WO 9509612A1
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Prior art keywords
nitric oxide
compound
pharmaceutically acceptable
group
branched chain
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PCT/US1994/011441
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English (en)
Inventor
Shawn J. Green
Larry K. Keefer
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Entremed, Inc.
THE GOVERNMENT OF THE UNITED STATES OF AMERICA represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES: National Institutes of Health
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Priority to AU79722/94A priority Critical patent/AU7972294A/en
Publication of WO1995009612A1 publication Critical patent/WO1995009612A1/fr

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • A61K9/127Liposomes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This invention relates to the treatment of disease, and more particularly to compositions and methods for treating diseases with nitric oxide.
  • the present invention is directed to the use of compounds which release nitric oxide in aqueous solutions, particularly nitric oxide/nucleophile complexes and their derivatives, to induce cytostasis and cytotoxicity so as to attenuate cell proliferation.
  • Certain infections particularly those caused by aggressive pathogens that can replicate within cells, have potentially life-threatening consequences for a wide variety of organisms including humans.
  • Many of these aggressive infections involve white cells, called macrophages, that play a major role in engulfing, or phagocytosing microorganisms such as bacteria.
  • Macrophages play a crucial role in the immune response to several pathologies including neoplastic, bacterial, fungal, parasitic, and viral diseases. Macrophages also maintain homeostatic function through involvement in antigen presentation, removal of aging red blood cells and tissue remodeling. Therefore, alterations in macrophage function due to any disease process can have severe and potentially life- threatening consequences.
  • invading microorganisms can survive and multiply in the cytoplasm or within intracellular vacuoles of the macrophage, thereby preventing the macrophage from responding appropriately to signals that normally activate the macrophage to kill and eliminate the intracellular pathogen. Instead, the infected macrophage now serves as the vehicle to promote the disease process. Accordingly, diseases that threaten macrophages may have significant impact on the immune response and are therefore potentially lethal.
  • Macrophage-based diseases include parasitic, fungal, bacterial and viral infections which deleteriously affect macrophages. These diseases account for a tremendous amount of suffering, loss of life, and a large percentage of world health problems. The economic cost of such infections in humans and in domesticated animals is staggering. Current approaches for combating these infections involve parenteral administration of high doses of drugs. Many infectious diseases are resistant to drug therapy (e.g. TB and malaria). For those pathogens which are drug-resistant high doses are necessary since the administered drugs are diluted in the circulatory system before reaching the desired site of action (inside the macrophage), and are also degraded in the liver. These high doses of drugs often cause a metabolic overload in the liver, with subsequent undesirable toxic side effects. There is a great need for new methods of combating macrophage- based diseases.
  • Lysosomes are vesicular structures that are functionally linked to the digestive capability of cells, . especially macrophages which are specialized for phagocytosis. Lysosomes contain high concentrations of hydrolytic enzymes in an acidic environment. Organisms such as Mycobacterium tuberculosis, can survive and multiply in lysosomes and their progeny phagolysosomes, and transform the macrophage from a disease fighting cell to a disease promoting cell.
  • Nitric oxide has recently been implicated in a variety of bioregulatory processes, including normal physiological control of blood pressure, macrophage-induced cytostasis and cytotoxicity, and neurotransmission (Moncada et al., "Nitric Oxide from L-Arginine: A Bioregulatory System,” Excerpta Medica. International Congress Series 897
  • a number of compounds have been developed which are capable of delivering nitric oxide, including compounds which release nitric oxide upon being metabolized and compounds which release nitric oxide in aqueous solution.
  • Those compounds which release nitric oxide upon being metabolized include the widely used nitrovasodilators glyceryl trinitrate and sodium nitroprusside (Ignarro et al., Pharmacol. Exp. Ther.. 218. 739-749 (1981); Ignarro, Annu. Rev. Pharmacol. Toxicol.. 30. 535-560 (1990); Kruszyna et al., Toxicol. Appl. Pharmacol.. £i, 429-438 (1987); Wilcox et al.. Chem. Res. ToxicoL. 3. 71 -76 ( 1990)).
  • Another compound, S-nitroso-N-acetylpenicillamine has been reported to release nitric oxide in solution and as being effective at inhibiting DNA synthesis (Garg et al., Biochem. and Biophys.
  • Nitric oxide/nucleophile complexes which release nitric oxide in aqueous solution are disclosed in U.S. Patents 4,954,526 and 5,039,705, as well as in pending U.S. patent applications 07/423,279 (filed October 18, 1989), 07/585,793 (filed September 20, 1990), 07/743,892 (filed August 12, 1991 ), 07/764,906 (filed September 24, 1991 ), 07/764,908 (filed September 24, 1991 ), and 07/858,885 (filed March 27, 1992), as being useful cardiovascular agents (see also Maragos et al., J. Med. Chem.. 34, 3242-3247 (1991)).
  • Nitric oxide in its pure form is a highly reactive gas having limited solubility in aqueous media (WHO Task Group on Environmental Health Criteria for Oxides of Nitrogen, Oxides of Nitrogen. Environmental Health Criteria 4 (World
  • Nitric oxide therefore, is difficult to introduce reliably into most biological systems without premature decomposition.
  • nitric oxide The difficulty in administering nitric oxide can be overcome in some cases by administering nitric oxide pharmacologically in prodrug form.
  • the compounds glyceryl trinitrate and sodium nitroprusside are relatively stable but release nitric oxide only on redox activation (Ignarro et al., J. Pharmacol. Exp. Ther.. 21 8. 739-749 ( 1981 ); Ignarro, Annu. Rev. Pharmacol. Toxicol.. 30. 535-560 ( 1990);
  • Nitric oxide gas can be formed metabolically from the amino acid L-arginine through the action of the enzyme nitric oxide synthase. Recent evidence shows that direct delivery of nitric oxide kills intracellular pathogens such as Mycobacterium tuberculosis. An ability to specifically deliver compounds capable of releasing nitric oxide to the desired site of infection within the macrophage would greatly enhance killing of intracellular pathogens.
  • liposomes are rapidly ingested by macrophages, particularly in the liver and spleen, where they are gradually degraded in lysosomal vacuoles. Segal, et al. (1974), Br. J. Exp. Pathol. 55, 320. It is also known that liposomes can be taken up by cells by non- receptor-mediated endocytosis, Fc-mediated endocytosis or phagocytosis, or complement-dependent phagocytosis. Wassef and Alving (1987), Methods in Enzymology 149, 124.
  • Liposomes are particles of lipoidal material that can be manufactured from a variety of chemicals and made in different sizes. They are non-toxic, biodegradable lipid spheres. West and Martin teach a method for producing liposomes of specific size no greater than 0.4 microns and concentration of about 250 ⁇ m/ml. U.S. Pat. No. 4,781,871 , ('871 ) ( 1988) "High Concentration Liposome Processing Method" which is hereby incorporated by reference. Drugs can be encapsulated within liposomes which have been used as delivery vehicles.
  • Loscalzo in U.S. Patents Nos. 5,002,964, (1991), 5,025,001 , (1991 ), and 5,187, 183, (1993) discloses the use of S-nitroso derivatives of angiotensin converting enzyme inhibitors for the treatment of various pathophysiological diseases.
  • Loscalzo in U.S. Pat. No. 5,002,964, (1991), teaches the use of S-nitroso derivatives of captopril for cardiovascular effects and for inhibition of platelet aggregation.
  • the present invention encompasses a method of controlling parasitic infection by inducing cytostasis and/or cytotoxicity among the cells. Specifically, the present invention involves exposing cells to a compound capable of releasing nitric oxide in an aqueous solution, particularly a nitric oxide/nucleophile complex or derivative thereof.
  • the present invention also encompasses a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier, including liposomes and polymers, and a therapeutically effective amount of a compound capable of releasing nitric oxide in an aqueous solution, particularly a nitric oxide/nucleophile complex or derivative thereof.
  • the pharmaceutical composition will generally contain an amount of the nitric oxide releasing compound sufficient to induce cytostasis or cytotoxicity among cells exposed to the pharmaceutical composition and has particular utility in antiparasitic, antifungal, and antibacterial treatments.
  • Yet another object of the invention is to use liposomes containing nitric oxide generators to treat macrophage-based diseases caused by viruses, bacteria, parasites, and fungi.
  • a further object of the present invention is to provide for intraarterial administration of liposomes and red blood cells containing nitric oxide generators to deliver high concentrations to specific organs or regions supplied by that artery.
  • Still another object of the invention is to aerosolize closed membranous vesicles containing nitric oxide generators for administration to the respiratory system through inhalation.
  • An additional object is to intracranially administer liposomes containing nitric oxide generators into the cerebroventricular system to combat bacterial or viral meningitis, and parasitic infections.
  • Another related object is to intracranially administer liposomes containing nitric oxide generators directly into tumors to facilitate intracranial tumor vascularization and regression.
  • a related object is to intradermally or subcutaneously inject liposomes containing nitric oxide generators to fight diseases including viruses, bacteria, parasites, and fungi.
  • Still another object of the invention is to administer liposomes containing nitric oxide generators via osmotic pumps.
  • a further object is to provide nitric oxide generator-containing compositions which do not generate nitric oxide immediately upon administration to a patient, but rather circulate in the body in a "pro-drug” form until it is activated to produce nitric oxide, for example at the site of inflammation.
  • the present invention is predicated on the discovery that cell proliferation can be attenuated or inhibited by exposing cells to a compound that is capable of releasing nitric oxide in an aqueous solution, specifically a nitric oxide/nucleophile complex or a derivative thereof.
  • the present invention concerns a method of controlling cell proliferation by exposing cells to a compound capable of releasing nitric oxide in an aqueous solution, as well as a pharmaceutical composition which includes a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound capable of releasing nitric oxide in an aqueous solution, particularly a nitric oxide/nucleophile complex or a derivative thereof.
  • the compounds that are capable of releasing nitric oxide in an aqueous solution in the context of the present invention preferably do so spontaneously upon contacting an aqueous environment, or in response to a shift in the local pH environment, and do not require activation through a redox reaction or electron transfer such as required for glyceryl trinitrate and sodium nitroprusside.
  • Some of the nitric oxide/nucleophile complexes useful in the context of the present invention do require activation by particular means, but only as necessary to free the nitric oxide releasing
  • X[N(0)NO]-group in the vicinity of the particular cells of interest.
  • covalent attachment of a protecting group to the anionic [N(0)NO]" function provides a means of postponing nitric oxide release until the molecule reaches an organ capable of metabolically removing the protecting group.
  • the action of the nitric oxide/nucleophile complex can be targeted to maximize the desired effect in treating microorganism-dependent disease states.
  • the nitric oxide releasing compound in the context of the present invention is capable of releasing nitric oxide in an aqueous solution, such a compound preferably releases nitric oxide under physiological conditions.
  • the compound capable of releasing nitric oxide in an aqueous solution is preferably a nitric oxide/nucleophile adduct, e.g., a complex of nitric oxide and a nucleophile, most preferably a nitric oxide/nucleophile complex which contains the anionic moiety X[N(0)NO] ⁇ , where X is any suitable nucleophile residue.
  • a nitric oxide/nucleophile adduct e.g., a complex of nitric oxide and a nucleophile, most preferably a nitric oxide/nucleophile complex which contains the anionic moiety X[N(0)NO] ⁇ , where X is any suitable nucleophile residue.
  • nitric oxide/nucleophile complexes are stable solids and are capable of delivering nitric oxide in a biologically usable form at a predictable rate.
  • nitric oxide/nucleophile complexes include those having the following formulas:
  • J is an organic or inorganic moiety, preferably a moiety which is not linked to the nitrogen of the remainder of the complex through a carbon atom
  • M + x is a pharmaceutically acceptable cation, where x is the valence of the cation, a is 1 or 2, and b and c are the smallest integers that result in a neutral compound, preferably such that the compound is not a salt of alanosine or dopastin, as described more fully in U.S.
  • Patent Number 5,212,204 which is hereby incorporated by reference in its entirety; Ri -NH+.(CH 2 ) x -N-[(CH 2 ) y Nj d -[(CH 2 ) z -N] b -R 3 R 2 N 2 O 2 - R 5 R 4
  • R j , R2, R3, R4, and R5 are the same or different and may be hydrogen, C3_ cycloalkyl, ⁇ . ⁇ 2 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-trichloro-t- butoxycarbonyl, and x, y, and z are the same or different and are integers from 2 to 12, as described more fully in U.S. Patent Number 5,155,137, which is hereby incorporated by reference in its entirety;
  • R and R7 are the same or different and may be hydrogen, C3-8 cycloalkyl, Cj _ i 2 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t- butoxycarbonyl, or 2,2,2-trichloro-t-butoxycarbonyl, f is an integer from 0 to 12, with the proviso that when B is the substituted piperazine moiety
  • N N -N 2 O 2 " then f is an integer from 2 to 12, as described more fully in U.S. Patent Number 5,250,550, which is hereby incorporated by reference in its entirety;
  • Rg is hydrogen, C3..8 cycloalkyl, C ⁇ . ⁇ 2 straight or branched chain alkyl, benzyl, benzoyl, phthaloyl, acetyl, trifluoroacetyl, p-toluyl, t-butoxycarbonyl, or 2,2,2-tri- chloro-t-butoxycarbonyl
  • R9 is hydrogen or a C1 -C12 straight or branched chain alkyl, and g is 2 to 6, as described more fully in U.S. Patent Number 5,250,550, which is hereby incorporated by reference in its entirety;
  • R ⁇ and R2 are independently selected from the group consisting of a straight chain or branched chain C ⁇ - C12 alkyl group and a benzyl group, preferably with no branch occurring on the alpha carbon atom, or else R j and R2 together with the nitrogen atom they are bonded to form a heterocyclic group
  • M +x is a pharmaceutically acceptable cation
  • x is the valence of the cation, as more fully described in U.S. Patent Nos. 5,039,705 and 5,208,233 and
  • M is a pharmaceutically acceptable metal, or where x is at least two, a mixture of two different pharmaceutically acceptable metals, L is a ligand different from (R R2N-N202) and is bound to at least one metal, R* and R ⁇ are each organic moieties and may be the same or different (preferably where M is copper, x is one, L is methanol, and y is one, that at least one of Rl or R2 is not ethyl), x is an integer of from 1 to 10, x' is the formal oxidation state of the metal M, and is an integer of from 1 to 6, y is an integer of from 1 to 18, and where y is at least 2, the ligands L may be the same or different, z is an integer of from 1 to 20, and K is a pharmaceutically acceptable counterion to render the compound neutral to the extent necessary, as described in U.S. Patent Application Serial Number 07/858,885; and
  • R is C2-8 lower alkyl, phenyl, benzyl, or C3 _ g cycloalkyl, any of which R groups may be substituted by one to three substituents, which are the same or different, selected from the group consisting of halo, hydroxy, Cj .g alkoxy, -NH2, -C(0)NH2, -CH(O), -C(0)OH, and -NO2,
  • X is a pharmaceutically acceptable cation, a pharmaceutically acceptable metal center, or a pharmaceutically acceptable organic group selected from the group consisting of Cj .g lower alkyl, -C(0)CH3, and -C(0)NH2, and y is one to three, consistent with the valence of X, as more fully described in
  • Another class of compounds useful in the present invention are those compounds comprising the nitric oxide/nucleophile adducts bound to a polymer, which release nitric oxide in a physiological environment, and to pharmaceutical compositions, including implants, patches and the like, incorporating the polymer-bound nitric oxide/nucleophile adduct compositions, and to methods of treating biological disorders with polymer-bound nitric oxide/nucleophile adduct compositions.
  • Such compounds are more fully described in U.S. Patent Application Serial Number 07/935,565.
  • bound to a polymer it is meant that the
  • N 2 ⁇ 2" functional group is associated with, part of, incorporated with or contained within the polymer matrix physically or chemically. Physical association or bonding of the N2 ⁇ 2" functional group to the polymer may be achieved by coprecipitation of the polymer with a nitric oxide/nucleophile complex as well as by covalent bonding of the N2 ⁇ 2 " group to the polymer. Chemical bonding of the N2 ⁇ 2" functional group to the polymer may be by, for example, covalent bonding of the nucleophile moiety of the nitric oxide/nucleophile adduct to the polymer such that the nucleophile residue to which the
  • N2 ⁇ 2 " group is attached forms part of the polymer itself, i.e., is in the polymer backbone or is attached to pendant groups on the polymer backbone.
  • the manner in which the nitric oxide-releasing N2 ⁇ 2" functional group is associated, part of, or incorporated with or contained within, i.e., "bound,” to the polymer is inconsequential to the present invention and all means of association, incorporation and bonding are contemplated herein.
  • the present invention also provides a pharmaceutical composition which includes a pharmaceutically acceptable carrier and a polymer having a nitric oxide-releasing N2O2" functional group bound to said polymer.
  • the polymer-bound nitric oxide-releasing N2 ⁇ 2" functional group compositions of the present invention may themselves function as a pharmaceutical composition, as for example, when the polymer-bound composition is in the form of an implant, stent, patch, or the like.
  • the invention further provides a method of treating biological disorders in which dosage with nitric oxide would be beneficial which comprises administering a composition comprising a polymer and a nitric oxide-releasing N2O2" functional group bound to said polymer in an amount sufficient to release a therapeutically effective amount of nitric oxide. It has been discovered that incorporation of the
  • N2O2" functional group into a polymeric matrix provides a polymer-bound nitric oxide/nucleophile adduct composition that can be applied with specificity to a biological site of interest.
  • Site specific application of the polymer-bound adduct composition enhances the selectivity of action of the nitric oxide releasing N2 ⁇ 2" functional group.
  • N2 ⁇ 2" functional groups attached to the polymer are necessarily localized, then the effect of their nitric oxide release will be concentrated in the tissues with which they are in contact. If the polymer is soluble, selectivity of action can still be arranged, for example, by attachment to or derivatization of an antibody specific to the target tissue.
  • N2 ⁇ 2" groups attachment of N2 ⁇ 2" groups to small peptides that mimic the recognition sequences of ligands for important receptors provides localized concentrated effect of nitric oxide release, as would attachment to oligonucleotides capable of site-specific interactions with target sequences in a nucleic acid.
  • incorporation of the N2 ⁇ 2 " functional group into a polymer matrix can reduce the propensity of the nitric oxide/nucleophile adduct for the relatively rapid release of nitric oxide. This prolongs the release of nitric oxide by the N2 ⁇ 2" functional group, and allows for efficient dosing to achieve a desired biological effect so the frequency of dosing can be reduced. While not being bound to any particular theory, it is believed that longevity of nitric oxide release in the polymer-bound nitric oxide/nucleophile adduct compositions of the present invention is to be attributed both to the physical structure of the composition and to electrostatic effects.
  • N2 ⁇ 2 " groups near the surface of the particle should be available for rapid release while those that are more deeply imbedded are sterically shielded, requiring more time and/or energy for the nitric oxide to work its way into the medium.
  • increasing positive charge in the vicinity of an N2 ⁇ 2" functional group also tends to increase the half-life of nitric oxide generation.
  • the mechanism of this rate retardation may be attributable simply to repulsive electrostatic interactions, i.e., increasing the number of
  • H + -repelling positive charges in the vicinity of the N2 ⁇ 2" groups inhibits attack of positively charged H+ ions on the N2 ⁇ 2" functional group and slows-the rate of its H + - catalyzed decomposition.
  • partially converted structures can be produced on less-than-exhaustive treatment with nitric oxide that after exposure to water contain a large number of positively charged ammonium centers surrounding the N2 ⁇ 2" group that electrostatically inhibit the approach of H + ions capable of initiating nitric oxide loss from the nitric oxide releasing N2 ⁇ 2" functional group.
  • RI and R2 are independently chosen from Cl -12 straight chain alkyl, Cl -12 alkoxy or acyloxy substituted straight chain alkyd, C2- 1 2 hydroxy or halo substituted straight chain alkyl, C3-12 branched chain alkyd, C3-12 hydroxy, halo, alkoxy, or acyloxy substituted branched chain alkyl, C3-12 straight chain olefinic and C3- 12 branched chain olefinic which are unsubstituted or substituted with hydroxy, alkoxy, acyloxy, halo or benzyl, or Rl and R2 together with the nitrogen atom to which they are bonded form a heterocyclic group, preferably a pyrrolidino, piperidino, piperazino or morpholino group, and R3 is a group selected from Cl -12 straight chain and C3-12 branched chain alkyl which are unsubstituted or substituted by hydroxy, halo,
  • polymers suitable for use in the present invention are polyolefins, such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, biopolymers such as peptides, proteins, oligonucleotides, antibodies and nucleic acids, starburst dendrimers, and the like.
  • polyolefins such as polystyrene, polypropylene, polyethylene, polytetrafluorethylene, polyvinylidene difluoride, polyvinylchloride, derivatized polyolefins such as polyethylenimine, polyethers, polyesters, polyamides such as nylon, polyurethanes, biopolymers such as peptides, proteins, oligonucleotides
  • the physical and structural characteristics of the polymers suitable for use in the present invention are not narrowly critical, but rather will depend on the end use application. It will be appreciated by those skilled in the art that where the polymer-bound nitric oxide/nucleophile adduct compositions of the present invention are intended for topical, dermal, percutaneous, or similar use, they need not be biodegradable. For some uses, such as ingestion or the like, it may be desirable that the polymer of the polymer-bound compositions slowly dissolves in a physiological environment or that it is biodegradable.
  • the polymer-bound nitric oxide releasing compositions of the present invention will find utility in a wide variety of applications and in a wide variety of forms depending on the biological disorder to be treated.
  • the polymer may itself be structurally sufficient to serve as an implant, patch, stent or the like.
  • the polymer-bound composition may be incorporated into other polymer matrices, substrates or the like, or it may be microencapsulated, or the like.
  • nitric oxide-releasing complexes having N2 ⁇ 2" functional groups may be bound to the polymer support in a number of different ways.
  • the compounds described above may be bound to the polymer by coprecipitation of such compounds with the polymer. Coprecipitation involves, for example, solubilizing both the polymer and the nitric oxide/nucleophile compound and evaporating the solvent.
  • nitric oxide releasing N2 ⁇ 2 " so functional groups may be bound to the polymer by formation of a nitric oxide/nucleophile complex of the types and having the formulas of those described above, in situ on the polymer.
  • the N2O2" functional group may be attached to an atom in the backbone of the polymer, or it may be attached to a group pendant to the polymer backbone, or it may simply be entrapped in the polymer matrix.
  • the polymer includes in its backbone sites which are capable of reacting with nitric oxide to bind the nitric oxide for future release.
  • the polymer includes nucleophilic nitrogen atoms which react with nitric oxide to form the N2 ⁇ 2"- functional group at the nitrogen in the backbone.
  • the N2 ⁇ 2"functional group is a group pendant to the polymer backbone
  • the polymer contains, or is derivatized with, a suitable nucleophilic residue capable of reacting with nitric oxide to form the N2O2" functionality. Reaction of the polymer which contains a suitable nucleophilic residue, or of the suitably derivatized polymer with nitric oxide thus provides a polymer-bound nitric oxide-releasing N2 ⁇ 2"functional group.
  • compositions are prepared that contain encapsulated nitric oxide generators, i.e. the nitric oxide generators are contained within closed membranous vesicles.
  • vesicle as used herein, means a small membrane enclosed sac containing fluid.
  • Vesicles of the present invention include any of the types of liposomes known in the art and red blood cells modified for use as drug delivery vehicles.
  • the compositions may also contain pharmaceutically acceptable excipients, such as buffers, solutions, lotions, oils, gels, emollients and emulsions.
  • nitric oxide/nucleophile complexes generally involves reacting nitric oxide with suitable nucleophiles and has been described in Drago, "Reactions of Nitrogen(II) Oxide,” in Free Radicals in Inorganic Chemistry. Advances in Chemistry Series, Number 36 (American Chemical Society: Washington, DC, 1962), pp.
  • the rate at which the nitric oxide/nucleophile complex releases nitric oxide is dependent on at least the pH of the aqueous solution, the temperature, and the specific nature of the nucleophile. In general, the more alkaline the medium and the lower the temperature, the slower the release of nitric oxide. The nature of the nucleophile influences the rate of nitric oxide release over a considerable range. The effect on cell proliferation of the compound capable of releasing nitric oxide, therefore, can be controlled by appropriate selection of the nitric oxide releasing compound.
  • the effect of a compound capable of releasing nitric oxide in an aqueous solution on cells is reversible in the sense that the addition of a compound which is capable of removing or scavenging nitric oxide from an aqueous solution by complexing or reacting with nitric oxide can counteract the inhibitory effect of the compound which releases the nitric oxide.
  • the effect on cell proliferation of the compound capable of releasing nitric oxide therefore, can be further controlled by use of such a nitric oxide scavenger compound in an appropriate quantity.
  • the present inventive method includes the administration to an animal, particularly a human, of a therapeutically effective amount of a compound capable of releasing nitric oxide in an aqueous solution, particularly a nitric oxide/nucleophile complex or derivative thereof.
  • a compound capable of releasing nitric oxide in an aqueous solution particularly a nitric oxide/nucleophile complex or derivative thereof.
  • nitric oxide releasing compound in the context of the present invention can be administered in any suitable manner, preferably with pharmaceutically acceptable carriers.
  • nitric oxide releasing compound in the context of the present invention to an animal
  • suitable methods of administering a nitric oxide releasing compound in the context of the present invention to an animal are available, and, although more than one route can be used to administer a particular compound, a particular route can provide a more immediate and more effective reaction than another route.
  • Pharmaceutically acceptable carriers are also well-known to those who are skilled in the art. The choice of carrier will be determined in part by the particular compound, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water or saline, (b) capsules, sachets or tablets, each containing a predetermined amount of the active ingredient, as solids or granules, (c) suspensions in an appropriate liquid, and (d) suitable emulsions.
  • liquid solutions such as an effective amount of the compound dissolved in diluents, such as water or saline
  • diluents such as water or saline
  • capsules, sachets or tablets each containing a predetermined amount of the active ingredient, as solids or granules
  • suspensions in an appropriate liquid and (d) suitable emulsions.
  • Tablet forms can include one or more of lactose, mannitol, corn starch, potato starch, microcrystalline cellulose, acacia, gelatin, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin or sucrose and acacia emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.
  • nitric oxide releasing compounds in the context of the present invention can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • Formu lations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the formulations can be presented in unit- dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the dose administered to an animal, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the animal over a reasonable time frame.
  • the dose will be determined by the strength of the particular compound employed and the condition of the animal, as well as the body weight of the animal to be treated.
  • the size of the dose also will be determined by the existence, nature, and extent of any adverse side-effects that might accompany the administration of a particular compound.
  • a "mega-dosing" regimen In the treatment of some individuals with the pharmaceutical composition of the present invention, it may be desirable to utilize a "mega-dosing" regimen.
  • a large dose of the pharmaceutical composition is administered to an individual, time is allowed for the active compound, i.e., the nitric oxide releasing compound, to act, and then a suitable reagent, e.g., a nitric oxide scavenger, is administered to the individual to render the active compound ineffective.
  • a suitable reagent e.g., a nitric oxide scavenger
  • the desirable extent of the inhibition of cell proliferation rate will depend on the particular condition or disease being treated, as well as the stability of the patient and possible side-effects.
  • the present invention provides for a wide range of the inhibition of the normal cell proliferation rate, e.g., from little inhibition to essentially full inhibition.
  • the cytostatic activity of a nitric oxide/nucleophile complex is generally related to the rate and extent of nitric oxide release. It is believed that those compounds which release nitric oxide slowly, such as spermine-bis(nitric oxide) adduct monohydrate and 3(n- propylamino)propylamine bis(nitric oxide) adduct, are more potent inhibitors of DNA synthesis than compounds which release nitric oxide more quickly, such as diethylamine- bis(nitric oxide) adduct sodium salt, isopropylamine-bis(nitric oxide) adduct sodium salt, and sodium trioxodinitrate(II) monohydrate (also known as "Angeli's salt").
  • nitric oxide/nucleophile complex which will generally vary up to two per [N(0)NO] moiety, apparently affects the potency of the nitric oxide/nucleophile complex, with compounds which release more nitric oxide per molecule having a greater cytostatic effect.
  • the cytostatic effect of a nitric oxide/nucleophile complex is also dependent on factors in addition to the rate and extent of nitric oxide release. Such factors include specificity of the delivery of nitric oxide generation compounds to localized sites, the mechanism by which the compound degrades, the degree of uptake by the exposed cells, and the affinity for cellular constituents. For example, spermine binds DNA which may play a role in the nitric oxide/spermine complex having a high cytostatic effect on tumor cells.
  • the present invention also has usefulness in prophylatic treatments.
  • the present invention provides nitric oxide generator-containing compositions and methods of using such compositions that are particularly useful for the treatment of infectious diseases by administering the nitric oxide generator- containing compositions to a human or animal suffering from the disease.
  • the administered nitric oxide generator- containing compositions produce localized and high concentrations of nitric oxide to kill infectious pathogens such as parasites, viruses, fungi, protozoa and bacteria.
  • the present invention includes a therapeutic nitric oxide generator-containing composition for treating disease comprising, vesicles impregnated with one or more nitric oxide generators, and a therapeutic method for treating a disease comprising, the step of administering to a human or animal suffering from a disease caused by an infectious microbe an amount of a composition comprising vesicles impregnated with one or more nitric oxide generators effective for killing the infectious microbe.
  • nitric oxide generators When nitric oxide generators contact inflammatory cells, such as macrophages, or inflamed areas of tissues, it is believed that the local inflammatory environment triggers the generation and release of nitric oxide. Without wanting to be bound by the following theory, it is believed that a localized changed in pH or the presence in high concentration of esterases and hydroxylases at the inflammatory site triggers the formation of nitric oxide by the nitric oxide generator. The localized delivery and high concentration of nitric oxide thus produced, damages or destroys harmful and infectious cells at the site of inflammation.
  • Desirable nitric oxide generators used in the encapsulated and non-encapsulated compositions of the present invention include, but are not limited to nitric oxide generators such as SPER/NO, DETA/NO, V-DEA/NO, S-DEA/NO, MOM-DEA/NO, acetoxy-DEA/NO, DEA/NO, SULFI/NO, OXI/NO, A-DEA/NO, M-DEA-NO, HE-DEA/NO, A-
  • Desirable compounds for use in the present invention include the spontaneous nitric oxide generator DETA/NO and the stable nitric oxide generator MOM-DEA/NO.
  • compositions containing nitric oxide generators eliminates these problems by assuring a high concentration of nitric oxide specifically within macrophages or at sites of inflammation. This targeted delivery of nitric oxide allows lower total dosages to be administered, thus reducing non-specific side effects, without loss of efficacy.
  • Liposomes are a desirable vehicle for administering nitric oxide generators because they are ingested by macrophages. Liposomes can be made by any method for making liposomes known in the art. These vesicles may be impregnated with any of the above-described nitric oxide releasing compounds or combinations thereof. The term "impregnated”, as used herein, means that one or more of the nitric oxide generator compounds is placed within the lumen or membrane of the liposome.
  • nitric oxide generators After administration of the vesicles to the human or animal in need of treatment, the nitric oxide generators undergo a chemical reaction to form nitric oxide, preferably at the site of inflammation or within macrophages, a location where infectious microbes commonly are found within the body. Inflammatory macrophages exhibit high phagocytic activity which may act to concentrate nitric oxide generator- containing vesicles, enhancing the therapeutic efficacy of the nitric oxide generated. Once liposomes bind to the macrophage surface, they are engulfed and internalized in phagolysomes. The pH environment of phagolyosomes is approximately pH 5-6.
  • the acidic pH promotes release of nitric oxide from the nitric oxide generator.
  • the nitric oxide so produced kills or damages the pathogen, thus reducing or eliminating the microbial infection.
  • the vesicles are selectively and preferentially taken up by macrophages, the production of nitric oxide often may be further enhanced within the macrophage by the action of enzymes.
  • Red blood cells optionally modified to enhance their uptake by macrophages, are impregnated with nitric oxide generators. Alteration of the phosphatidyl serine content of red blood cell membranes enhances their uptake by macrophages.
  • Red blood cells are loaded with nitric oxide generators according to methods known in the art. For example, RBCs can be made leaky in the presence of nitric oxide generators and the loss of integrity of the cell membrane permits the nitric oxide generators to enter the lumen of the cells.
  • RBCs may be loaded with nitric oxide generators using electroporation techniques well known in the art. Aging red blood cells are normally phagocytosed by macrophages.
  • nitric oxide generators by red blood cells is an effective method for combating splenic disease.
  • liposomes described above phagocytosis of the RBC enhances production of free nitric oxide within the macrophage.
  • red blood cells encapsulating nitric oxide generators can be delivered via the splenic artery to maximize their uptake into the spleen.
  • Nitric oxide generator-containing vesicles are administered via several different routes including, but not limited to, the following; intravenous, intraperitoneal, intracranial, inhalation, topical, transdermal, subcutaneous, and also by injection into tumors. Administration takes the form of direct injection, infusion, release from osmotic pumps, and release from subcutaneous implants. For example, administration through the aerosol route is highly beneficial to humans or animals with pulmonary infections. Various bacterial, protozoan, fungal, viral, and parasitic infections of the respiratory system that involve macrophages are attacked in this fashion.
  • Skin diseases caused by bacteria, viruses, fungi protozoa and parasites may be treated by topical administration of nitric oxide generator-containing compositions, such as liposomes encapsulating nitric oxide generators or non- encapsulated nitric oxide generators.
  • nitric oxide generator-containing compositions such as liposomes encapsulating nitric oxide generators or non- encapsulated nitric oxide generators.
  • An example of such a skin disease is cutaneously erupting neural viruses, such as Herpes.
  • nitric oxide generators Following uptake of liposomes or red blood cells that contain nitric oxide generators by macrophages, the nitric oxide generators undergo chemical modification within the macrophage to produce free nitric oxide. The resultant generation of nitric oxide occurs within lysosomes and is extremely effective in killing intracellular pathogens. This invention may also provide therapeutic treatment for otherwise untreatable diseases.
  • the liposome compositions and methods described in this invention are employed for a variety of viral, bacterial, fungal, and parasitic infections. Some of these include, but are not limited to Mycobacterium tuberculosis, toxoplasmosis, AIDS, and diseases caused by Leishmania and Cryptococcus neoformans.
  • EXAMPLE I This Example illustrates the formation of a polymer containing nitric oxide-releasing N2 ⁇ 2" groups that are attached to nucleophile residues pendant on the polymer backbone.
  • n- propyl-l,3-propanediamine was warmed to 60°C in an oil bath and swirled periodically for 5 days. The polymer was then filtered, washed repeatedly with water then methanol and finally dichloromethane and dried in vacuo for 24 hrs.
  • nitric oxide can be recovered from the polymer described in this Example.
  • the amount of nitric oxide regenerated when the polymer of Example I was treated with acid was measured with a chemiluminescence detector.
  • the solid sample was placed in a reactor vessel, which was then purged continuously with helium such that the effluent gases were swept into a nitric oxide-selective Thermal Energy Analyzer Model 502 (Thermo Electron Corp., Waltham, MA).
  • nitric oxide Only small amounts of nitric oxide were evolved from the solid itself, but when 2 mL of 10 mM sulfuric acid was injected via a septum, a sudden pulse of nitric oxide appeared. Integration of this apparently first order generation of nitric oxide over time indicated that 1 1 nmol of nitric oxide was recovered from 1 mg of polymer.
  • the reaction was repeated using 10 mM phosphate buffer at pH 7.4 in place of the sulfuric acid to verify the slow release of nitric oxide at physiological pH.
  • the chemiluminescence detector revealed that nitric oxide was generated very much more slowly.
  • EXAMPLE II This Example illustrates the preparation of a polymer-bound nitric oxide/nucleophile complex by coprecipitation of a monomeric form thereof with a polymer.
  • EXAMPLE HI This Example illustrates the preparation of a polymer-bound nitric oxide/nucleophile adduct in which the N2 ⁇ 2" group is bound directly to an atom in the polymer backbone.
  • Liposomes are prepared by methods known in the art. Generally liposomes are prepared by dissolving the lipids that are to constitute the liposome membrane in a solvent such as chloroform. Other solvents, or solvent combinations, such as chloroform and methanol, may be used to dissolve the lipids. Liposomes may contain any combination of a number of lipids, including cholesterol, phosphatidylcholine, dimyristoyl phosphatidylcholine, phosphatidylserine, phosphatidic acid, phosphatidylinositol, phosphatidylethanolamine, cardiolipin, and lecithin.
  • glycolipids and lipopolysaccharides may also be used as components of the liposome membrane to make the liposome appear foreign and, therefore, antigenic.
  • glycolipids include gangliosides and digalactosyl diglyceride.
  • An example of a possible lipopolysaccharide is lipid A.
  • Making the liposome antigenic may concentrate liposomes at sites of inflammation and promote uptake of the liposome by immune cells such as macrophages.
  • liposomes may contain phospholipid and cholesterol in a ratio of 1 :0.75, which approximates the ratio of phospholipid to cholesterol found in RBCs.
  • Liposomes containing in their membrane phosphatidylcholine and cholesterol in the range of 1 : 1 to 1 :2.5 are also routinely prepared.
  • the lipid solutions are combined in a volume suitable to permit thorough agitation; generally a ten fold greater volume than the anticipated final volume may be used.
  • Solvent is removed, e.g. by rotary evaporation under vacuum.
  • the dried lipids are resuspended in an encapsulating solution, which contains the nitric oxide generator to be trapped within the liposome, by vigorous agitation such as vortexing.
  • the liposomes that result are multilamellar.
  • unencapsulated material may be washed away, for example by dialysis or gentle centrifugation. A more detailed description follows.
  • Dioleoylphosphatidylcholine Bovine brain phosphatidylserine (BBPS): and cholesterol, in mole ratios of 7:3:7.5, respectively. Dissolved lipids are aliquoted in these ratios into glass, pear-shaped flasks and the bulk of the chloroform solvent was removed by rotary evaporation. Trace solvent was removed by vacuum desiccation. Nitric oxide generators dissolved in calcium/magnesium-free phosphate-buffered saline (PBS) was added to the dry lipid and the mixture vortexed vigorously for 1 minute to form the liposomes. The mixture was incubated at room temperature for 2 hours to allow hydration of the lipids.
  • PBS calcium/magnesium-free phosphate-buffered saline
  • the liposomes were then washed with 20 volumes of PBS by centrifugation at 15,000 rpm for 30 minutes in an SS-34 rotor in a Sorvall high-speed centrifuge. Liposome pellets were resuspended with PBS to 10 mM with respect to total phospholipid.
  • Quantitation of Encapsulated Nitric Oxide Generators Quantitation of encapsulated nitric oxide generators was carried out using a Perkin-Elmer dual-beam spectrophotometer programmed for second derivative quantitative scanning. Each nitric oxide generator was scanned to determine the precise wavelengths for second derivative scanning. Standards curves were generated for each nitric oxide generator and were used for quantitating liposome- encapsulated nitric oxide generators. For the actual quantitative scan of the encapsulated nitric oxide generators, liposomes containing either nitric oxide generator or PBS were diluted 1 :25 with PBS.
  • control preparation was placed in the reference curette to correct for the absorbance by the liposomes, and the samples were scanned from 280 to 220 nm using the predetermined wavelengths for second derivative calculation. Results were calculated by the software provided with the spectrophotometer, as modified by the users.
  • nitric oxide generators are stabilized by storage at high pH (10 mM NaOH) and low temperature (-20°C).
  • pH 10 mM NaOH
  • low temperature 20°C
  • each generator was dissolved in PBS (neutral buffer) and the absorbance at peak wavelength (as determined by absorbance scan) immediately and after incubation at room temperature for 24 hours. Results for four nitric oxide generators are given below.
  • a growth-inhibition curve experiment was conducted to determine the dose-dependent effects on incubating various pathogenic microbes in the presence of increasing concentrations of nitric oxide generators.
  • Table 2 show the dosages at which growth of each of Candida albicans, Francisella tularensis, and Leishmania major is inhibited 50% (IC50).
  • Selected microorganisms were cultured in defined liquid growth media suitable for each microbe that contained the indicated nitric oxide generator. Control cultures were inoculated simultaneously into defined liquid growth media without any nitric oxide generator. The nitric oxide generator compounds initially were dissolved in lOmM NaOH, then added to the media to the desired concentration.
  • nitric oxide releasing compounds NONOates
  • liposomes may facilitate this process because they are readily taken up by macrophages.
  • NON-ENCAPSULATED NON-ENCAPSULATED.
  • SPERM/NO, DETA/NO, and Acetyl-DEA/NO was found to be 6.7-, 7.2-, and 8.9-times, respectively, more effective at blocking Leishmania major growth in vitro as glucantime.
  • Glucantime is the current and approved drug of choice for treatment of Leishmaniasis in humans.
  • Assessment of inhibition of parasite growth in vitro is based on comparing equivalent molar concentrations of NONOnates and glucantime. All other NONOnates tested were significantly less effective at directly inhibiting the growth of Leishmania in vitro.
  • Plasmodium falciparum the causative agent of human malaria. Since there are no relevant anti ⁇ malarial agents to compare, we determined the IC50 and IC90 in vitro. Again, all 20 compounds were tested, and consistent with the Leishmania survey only DETA/NO, SPERM/NO, and Acetyl-DEA/NO were effective.

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Abstract

Cette invention concerne des compositions capables de libérer de l'oxyde nitrique et des procédés thérapeutiques utilisant cet oxyde nitrique pour le traitement de maladies dues à des micro-organismes. La composition comporte un ou plusieurs générateurs d'oxyde nitrique, de préférence encapsulés dans des vésicules, telles que des liposomes. Ces compositions sont administrées à l'homme et aux animaux par différentes voies pour traiter des maladies infectieuses causées par des microbes pathogènes.
PCT/US1994/011441 1993-10-07 1994-10-07 Substances encapsulees et non encapsulees pouvant liberer de l'oxyde nitrique et utilisees comme agents antimicrobiens WO1995009612A1 (fr)

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EP0979073A1 (fr) * 1997-03-31 2000-02-16 The Children's Medical Center Corporation Nitrosylation effectuee pour inactiver des enzymes apoptotiques
WO2000030659A1 (fr) * 1998-11-23 2000-06-02 Pulmonox Medical Corporation Procede et appareil permettant de traiter des infections respiratoires par inhalation d'oxyde nitrique
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US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
WO2003032928A2 (fr) * 2001-10-19 2003-04-24 Barts And The London Nhs Trust Composition therapeutique et son utilisation
US6793644B2 (en) 2000-12-26 2004-09-21 Sensormedics Corporation Device and method for treatment of surface infections with nitric oxide
WO2007054373A1 (fr) * 2005-11-14 2007-05-18 Nolabs Ab Composition a base d'oxyde nitrique et son utilisation pour le traitement du cancer et la prophylaxie et le traitement d'une infection des voies urinaires
US7335181B2 (en) 2000-12-26 2008-02-26 Pulmonox Technologies Corporation Nitric oxide decontamination of the upper respiratory tract
WO2008095312A1 (fr) * 2007-02-09 2008-08-14 Pulmonox Technologies Corporation Utilisation d'acide nitrique gazeux à dosage à forte concentration
WO2010002450A2 (fr) * 2008-07-03 2010-01-07 Ecole Polytechnique Federale De Lausanne Micelles pour délivrer de l’oxyde nitrique
US20100040703A1 (en) * 2008-08-13 2010-02-18 Chris Miller Use of nitric oxide
US20120199123A1 (en) * 2004-05-11 2012-08-09 Pulmonox Technologies Corporation Intermittent dosing of nitric oxide gas
US9011935B2 (en) 2006-04-12 2015-04-21 Barts Health National Health Service Trust Therapeutic composition and use
WO2018132371A2 (fr) 2017-01-10 2018-07-19 United Therapeutics Corporation Méthodes et compositions pour le traitement de l'hypertension pulmonaire
US20190345099A1 (en) * 2016-06-22 2019-11-14 MedChem Partners, LLC Nitric oxide donors

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US6875840B2 (en) 1996-08-02 2005-04-05 Duke University Polymers for delivering nitric oxide in vivo
US7417109B2 (en) 1996-08-02 2008-08-26 Duke University Polymers for delivering nitric oxide in vivo
US7087709B2 (en) 1996-08-02 2006-08-08 Duke University Polymers for delivering nitric oxide in vivo
US6673891B2 (en) 1996-08-02 2004-01-06 Duke University Polymers for delivering nitric oxide in vivo
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
US6403759B2 (en) 1996-08-02 2002-06-11 Duke University Polymers for delivering nitric oxide in vivo
EP0946160A1 (fr) * 1996-08-27 1999-10-06 The University of Akron Polyamine esters lipophiles permettant l'apport de monoxyde d'azote cible sur un site a des fins pharmaceutiques
EP0946160A4 (fr) * 1996-08-27 2007-05-09 Univ Akron Polyamine esters lipophiles permettant l'apport de monoxyde d'azote cible sur un site a des fins pharmaceutiques
EP0979073A1 (fr) * 1997-03-31 2000-02-16 The Children's Medical Center Corporation Nitrosylation effectuee pour inactiver des enzymes apoptotiques
EP0979073A4 (fr) * 1997-03-31 2004-04-07 Childrens Medical Center Nitrosylation effectuee pour inactiver des enzymes apoptotiques
WO2000030659A1 (fr) * 1998-11-23 2000-06-02 Pulmonox Medical Corporation Procede et appareil permettant de traiter des infections respiratoires par inhalation d'oxyde nitrique
US6593339B1 (en) 1999-06-01 2003-07-15 Astrazeneca Ab Use of compounds as antibacterial agents
WO2000072838A1 (fr) * 1999-06-01 2000-12-07 Astrazeneca Ab Nouvelle utilisation de composes comme agents antibacteriens
AU780678B2 (en) * 1999-06-01 2005-04-07 Astrazeneca Ab New use of compounds as antibacterial agents
US6793644B2 (en) 2000-12-26 2004-09-21 Sensormedics Corporation Device and method for treatment of surface infections with nitric oxide
US7335181B2 (en) 2000-12-26 2008-02-26 Pulmonox Technologies Corporation Nitric oxide decontamination of the upper respiratory tract
WO2003032928A3 (fr) * 2001-10-19 2003-09-18 Barts & London Nhs Trust Composition therapeutique et son utilisation
WO2003032928A2 (fr) * 2001-10-19 2003-04-24 Barts And The London Nhs Trust Composition therapeutique et son utilisation
AU2002334190B2 (en) * 2001-10-19 2008-12-11 Barts And The London Nhs Trust Therapeutic composition and use
JP2005508957A (ja) * 2001-10-19 2005-04-07 バーツ アンド ザ ロンドン エヌエイチエス トラスト 治療用組成物および用途
US9095534B2 (en) * 2004-05-11 2015-08-04 Sensormedics Corporation Intermittent dosing of nitric oxide gas
US20120199123A1 (en) * 2004-05-11 2012-08-09 Pulmonox Technologies Corporation Intermittent dosing of nitric oxide gas
EP1790335A1 (fr) * 2005-11-14 2007-05-30 NOLabs AB Une composition et son usage pour la production d'un médicament pour traiter, traiter prophylactiquement et pour prévenir le cancer et/ou les infections des voies urinaires
WO2007054373A1 (fr) * 2005-11-14 2007-05-18 Nolabs Ab Composition a base d'oxyde nitrique et son utilisation pour le traitement du cancer et la prophylaxie et le traitement d'une infection des voies urinaires
US9011935B2 (en) 2006-04-12 2015-04-21 Barts Health National Health Service Trust Therapeutic composition and use
WO2008095312A1 (fr) * 2007-02-09 2008-08-14 Pulmonox Technologies Corporation Utilisation d'acide nitrique gazeux à dosage à forte concentration
WO2010002450A2 (fr) * 2008-07-03 2010-01-07 Ecole Polytechnique Federale De Lausanne Micelles pour délivrer de l’oxyde nitrique
WO2010002450A3 (fr) * 2008-07-03 2010-03-25 Ecole Polytechnique Federale De Lausanne Micelles pour délivrer de l’oxyde nitrique
US8852640B2 (en) 2008-07-03 2014-10-07 Ecole Polytechnique Federale De Lausanne (Epfl) Micelles for delivery of nitric oxide
US20100040703A1 (en) * 2008-08-13 2010-02-18 Chris Miller Use of nitric oxide
US20190345099A1 (en) * 2016-06-22 2019-11-14 MedChem Partners, LLC Nitric oxide donors
US11148999B2 (en) * 2016-06-22 2021-10-19 MedChem Partners, LLC Nitric oxide donors
WO2018132371A2 (fr) 2017-01-10 2018-07-19 United Therapeutics Corporation Méthodes et compositions pour le traitement de l'hypertension pulmonaire

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