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WO1997032585A1 - Procedes therapeutiques combinatoires utilisant des piegeurs de monoxyde d'azote et compositions utiles dans ces procedes - Google Patents

Procedes therapeutiques combinatoires utilisant des piegeurs de monoxyde d'azote et compositions utiles dans ces procedes Download PDF

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Publication number
WO1997032585A1
WO1997032585A1 PCT/US1997/004131 US9704131W WO9732585A1 WO 1997032585 A1 WO1997032585 A1 WO 1997032585A1 US 9704131 W US9704131 W US 9704131W WO 9732585 A1 WO9732585 A1 WO 9732585A1
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Prior art keywords
nitric oxide
inhibitors
agents
substituted
composition according
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PCT/US1997/004131
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English (en)
Inventor
Ching-San Lai
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Medinox, Inc.
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Application filed by Medinox, Inc. filed Critical Medinox, Inc.
Priority to AU22131/97A priority Critical patent/AU2213197A/en
Priority to JP9532042A priority patent/JP2000506170A/ja
Publication of WO1997032585A1 publication Critical patent/WO1997032585A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents
    • 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
    • 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

  • the present invention relates to methods for directly or indirectly treating the production of species which induce the expression of nitric oxide synthase in mammals.
  • the present invention relates to methods for inactivating such species, or inhibiting the production of such species, while, at the same time, reducing nitric oxide levels, by co-administration of agents which inactivate (or inhibit the production of) such species, along with a dithiocarbamate compound as a scavenger of overproduced nitric oxide.
  • the present invention relates to reducing elevated nitric oxide levels associated with infectious and/or inflammatory conditions (and the treatment thereof) , employing a combinational therapeutic method wherein an agent for the treatment of the infectious and/or inflammatory condition is co-administered along with a dithiocarbamate compound as a scavenger of overproduced nitric oxide.
  • the present invention relates to compositions and formulations useful in the methods disclosed herein.
  • nitric oxide a gaseous free- radical
  • Nitric oxide is formed from the terminal guanidino nitrogen atom of L-arginine by nitric oxide synthase (NOS; see, for example, Rodeberg et al., in Am. J. Surg. 170:292-303 (1995), and Bredt and Snyder in Ann. Rev. Biochem. 63:175-95 (1994)).
  • NOS nitric oxide synthase
  • a low output of • NO is produced by the constitutive, calcium-dependent NOS isoform (cNOS) present in numerous cells, including endothelium and neurons.
  • cNOS constitutive, calcium-dependent NOS isoform
  • This low level of nitric oxide is involved in a variety of regulatory processes, e.g., blood vessel homeostasis, neuronal communication and immune system function.
  • a high output of -NO is produced by the inducible, calcium-independent NOS isoform (iNOS) which is expressed in numerous cell types, including endothelial cells, smooth muscle cells and macrophages.
  • Nitric oxide can therefore be seen to be a mixed blessing, being very desirable when present in small amounts, while potentially being highly detrimental when produced in excessive quantities.
  • Nitric oxide is a potent vasodilator (see, for example, Palmer in Arch. Sur . 128:396-401 (1993) and Radomski & Moncada in Thromb. Haemos. 70:36-41 (1993).
  • -NO produced by the endothelium diffuses isotropically in all directions into adjacent tissues.
  • •NO diffuses into the vascular smooth muscle, it binds to guanylate cyclase enzyme, which catalyzes the production of cGMP, inducing vasodilation (see, for example, Ignarro, L.J., Ann. Rev. Toxicol. 30:535-560 (1990); Moncada, S., Acta Physiol. Scand.
  • nitric oxide causes an extreme drop in blood pressure, resulting in insufficient tissue perfusion and organ failure, syndromes that are associated with many diseases and/or conditions (e.g. , septic shock, overexpression of cytokines, allograft rejection, and the like) .
  • the overproduction of nitric oxide is triggered by a number of stimuli, such as, the overproduction of inflammatory cytokines (e.g., tumor necrosis factor (TNF), interleukin-1 (IL-l) , interferons, endotoxin, and the like) .
  • TNF tumor necrosis factor
  • IL-1 interleukin-1
  • Inflammatory cytokines e.g., TNF, interleukins or interferons
  • infectious agents e.g., endotoxin
  • nitric oxide overproduction by inducing transcription of the inducible nitric oxide synthase gene, leading to the production of inducible nitric oxide synthase, which in turn results in the overproduction of nitric oxide.
  • the production of nitric oxide by the above- described pathway can be disrupted in a variety of ways.
  • TNF production peaks at about 1-2 hours. Therefore, in order to be effective, anti-TNF antibodies would have to be administered at an early stage after infection, indeed, in many clinical settings, patients are likely to already have been infected with bacteria prior to being admitted. Accordingly, such therapeutic methods have met with only limited success.
  • NOS substrate or product analogue inhibitors of the enzyme
  • rodent studies show that inhibition of the production of nitric oxide causes intrauterine growth retardation and hind-limb disruptions in rats (see, for example, Diket et al., in Am. J. Obstet. Gynecol. 171:1243-1250 (1994)).
  • the inhibition of nitric oxide synthesis during endotoxemia has also been shown to be detrimental (see, for example, Minnard et al., in Arch. Surg.
  • combinational therapeutic methods have been developed for the in vivo inactivation or inhibition of formation (either directly or indirectly) of species which induce the expression of inducible nitric oxide synthase, as well as reducing nitric oxide levels produced as a result of -NO synthase expression.
  • combinational therapeutic methods have been developed which can be employed, for example, for the treatment of infectious and/or inflammatory conditions.
  • the effectiveness of many therapeutic agents used for the treatment of infectious and/or inflammatory conditions can be enhanced by co-administration thereof in combination with dithiocarbamate-containing nitric oxide scavenger(s) .
  • the present invention employs a combination of inactivation (and/or inhibition) and scavenging approach whereby the stimulus of nitric oxide synthase expression is inactivated and/or expression thereof is inhibited, and overproduced nitric oxide is bound in vivo to a suitable nitric oxide scavenger.
  • the resulting complexes render the stimulus of nitric oxide synthase expression inactive (or inhibit the production thereof) , while also rendering the resulting nitric oxide harmless.
  • the resulting complexes are eventually excreted in the urine of the host.
  • a suitable nitric oxide scavenger is co-administered along with a therapeutic agent which may promote nitric oxide formation, thereby providing a protective affect against the otherwise detrimental effects of nitric oxide overproduction.
  • compositions and formulations useful for carrying out the above-described methods there have been developed compositions and formulations useful for carrying out the above-described methods.
  • An exemplary nitric oxide scavenger contemplated for use in the practice of the present invention is a dithiocarbamate-ferrous iron complex.
  • This complex binds to -NO, forming a stable, water-soluble dithiocarbamate- iron-NO complex having a characteristic three-line spectrum (indicative of a mononitrosyl-Fe complex) which can readily be detected at ambient temperatures by electron paramagnetic resonance (EPR) spectroscopy (See Komarov et al., in Biochem. Biophys. Res. Commun. 195:1191-1198 (1993); and Lai and Komarov, FEBS Lett..345:120-124 f (1994)).
  • EPR electron paramagnetic resonance
  • the present invention relates to combinational therapeutic methods for treating the production of species which induce the expression of nitric oxide synthase in mammals.
  • a dual attack is mounted against a variety of stimuli which lead to the production of dangerously high in vivo levels of # N0.
  • Combinations of agents contemplated for use in the practice of the present invention i.e., agents capable of inactivating species which induce expression of inducible nitric oxide, or agents which inhibit the production of such species, or therapeutically useful agents which also induce nitric oxide production, and dithiocarbamate-containing nitric oxide scavengers
  • agents contemplated for use in the practice of the present invention i.e., agents capable of inactivating species which induce expression of inducible nitric oxide, or agents which inhibit the production of such species, or therapeutically useful agents which also induce nitric oxide production, and dithiocarbamate-containing nitric oxide scavengers
  • the agent capable of inactivating (or inhibiting the production of) species which induce expression of inducible nitric oxide and • NO scavengers interact with the stimulus or stimuli of nitric oxide synthase expression and in vivo produced -NO, respectively, forming a complex between said species and said agent, as well as a stable dithiocarbamate-metal-NO complex.
  • free -NO is a potent vasodilator
  • -NO chelated with dithiocarbamate-iron complexes is not.
  • the NO-containing complex is then filtered through the kidneys, concentrated in the urine, and eventually excreted by the subject, thereby reducing in vivo -NO levels.
  • the present invention relates to reducing elevated nitric oxide levels associated with infectious and/or inflammatory conditions (and the treatment thereof) .
  • a combinational therapeutic method is employed wherein an agent for the treatment of an infectious and/or inflammatory condition is co-administered along with a dithiocarbamate compound as a scavenger of overproduced nitric oxide.
  • Figure 1 illustrates the effects of endotoxin (LPS-4 mg/kg) treatment on mean arterial pressure (MAP) with and without [(MGD) 2 /Fe] treatment.
  • LPS-4 mg/kg mean arterial pressure
  • MAP mean arterial pressure
  • MMD mean arterial pressure
  • the invention method comprises directly or indirectly treating the production of species which induce the expression of inducible nitric oxide synthase in a subject.
  • invention methods comprise: co-administering to a subject an effective amount of a combination of at least one agent capable of directly or indirectly inactivating said species, or inhibiting production of said species, and at least one dithiocarbamate-containing nitric oxide scavenger.
  • combinational therapeutic methods employing an effective amount of a combination of at least one treating agent useful for the treatment of infectious and/or inflammatory conditions, and at least one dithiocarbamate-containing nitric oxide scavenger. It has been found that the above-described combination is more effective for the treatment of infectious and/or inflammatory conditions than is the treating agent alone.
  • Dithiocarbamate-containing nitric oxide scavengers contemplated for use in the practice of the present invention include any physiologically compatible derivative of the dithiocarbamate moiety (i.e., (R) 2 N-C(S)-SH) .
  • Such compounds can be described with reference to the following generic structure (I) :
  • each R, and R 2 is independently selected from a C, up to C 18 alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, substituted alkylaryl, arylalkyl, substituted arylalkyl, arylalkenyl, substituted arylalkenyl, arylalkynyl, substituted arylalkynyl, aroyl, substituted aroyl, acyl, substituted acyl or R 1 and R 2 can cooperate to form a 5-, 6- or 7-membered ring including N, R 1 and R g , x is 1 or 2, and
  • M is a monovalent cation when x is l, or M is a physiologically compatible divalent or trivalent transition metal cation when x is 2.
  • R a C 2 up to C 8 alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, pyridinyl, pyrrolidinyl, amino, amido, hydroxy or nitro,
  • *2 is selected from a C 1 up to i C 6 alkyl or substituted alkyl , or R 2 can cooperate with R 1 to form a 5- , 6- or 7-membered ring including N, R 2 and R 1. and
  • R. a C 2 up to C 8 alkyl or substituted alkyl, wherein the substituents are selected from carboxyl, acetyl, amido or hydroxy
  • R 2 a C 1 up to C 4 alkyl or substituted alkyl
  • R, and R 2 cooperate to form a 5-, 6- or 7- membered ring
  • the combination of R, and R 2 can be a variety of saturated or unsaturated 4, 5 or 6 atom bridging species selected from alkenylene or -0-, -S-,-C(0)- and/or -N(R)- containing alkylene moieties, wherein R is hydrogen or a lower alkyl moiety.
  • Monovalent cations contemplated for incorporation into compounds of structure (I) include H + , Na * , NH 4 * , tetraalkyl ammonium, and the like.
  • Physiologically compatible divalent or trivalent transition metal cations contemplated for incorporation into the above compounds include charged forms of iron, cobalt, copper, manganese, or the like (e.g., Fe *2 , Fe *3 , Co *2 , Co* 3 , Cu *2 , Mn *2 or Mn* 3 ) .
  • the ratio of dithiocarbamate-species to counter-ion M can vary widely.
  • substituted alkyl comprises alkyl groups further bearing one or more substituents selected from hydroxy, alkoxy (of a lower alkyl group; wherein a lower alkyl group has about 1-4 carbon atoms) , mercapto (of a lower alkyl group), cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy, substituted aryloxy, halogen, trifluoromethyl, cyano, nitro, nitrone, amino, amido, -C(0)H, acyl, oxyacyl, carboxyl, carbamate, sulfonyl, sulfonamide, sulfuryl, and the like.
  • cycloalkyl refers to cyclic ring-containing groups containing in the range of about 3 up to 8 carbon atoms
  • substituted cycloalkyl refers to cycloalkyl groups further bearing one or more substituents as set forth above.
  • alkenyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon double bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkenyl refers to alkenyl groups further bearing one or more substituents as set forth above.
  • alkynyl refers to straight or branched chain hydrocarbyl groups having at least one carbon-carbon triple bond, and having in the range of about 2 up to 12 carbon atoms
  • substituted alkynyl refers to alkynyl groups further bearing one or more substituents as set forth above.
  • aryl refers to aromatic groups having in the range of 6 up to 14 carbon atoms and "substituted aryl” refers to aryl groups further bearing one or more substituents as set forth above.
  • alkylaryl refers to alkyl- substituted aryl groups and "substituted alkylaryl” refers to alkylaryl groups further bearing one or more substituents as set forth above.
  • arylalkyl refers to aryl- substituted alkyl groups and “substituted arylalkyl” refers to arylalkyl groups further bearing one or more substituents as set forth above.
  • arylalkenyl refers to aryl- substituted alkenyl groups and "substituted arylalkenyl” refers to arylalkenyl groups further bearing one or more substituents as set forth above.
  • arylalkynyl refers to aryl- substituted alkynyl groups and "substituted arylalkynyl” refers to arylalkynyl groups further bearing one or more substituents as set forth above.
  • aroyl refers to aryl- carbonyl species such as benzoyi and "substituted aroyl” refers to aroyl groups further bearing one or more substituents as set forth above.
  • heterocyclic refers to cyclic (i.e., ring-containing) groups containing one or more heteroatoms (e.g., N, 0, S, or the like) as part of the ring structure, and having in the range of 3 up to 14 carbon atoms and "substituted heterocyclic” refers to heterocyclic groups further bearing one or more substituents as set forth above.
  • heteroatoms e.g., N, 0, S, or the like
  • acyl refers to alkyl- carbonyl species.
  • halogen refers to fluoride, chloride, bromide or iodide atoms.
  • Induction of expression of inducible nitric oxide synthase, and hence, overproduction of nitric oxide is associated with a wide range of disease states and/or indications, such as, for example, septic shock, ischemia, administration of cytokines, overexpression of cytokines, ulcers, inflammatory bowel disease (e.g., ulcerative colitis or Crohn's disease) , diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis, allograft rejection, encephalomyelitis, meningitis, pancreatitis, peritonitis, vasculitis, lymphocytic choriomeningitis , glomerul ⁇ nephritis, uveitis, ileitis, liver inflammation, renal inflammation, hemorrhagic shock, anaphylactic shock, burn, infection (including bacterial, viral, fungal and parasitic infections) , hemodialysis, chronic fatigue syndrome, stroke, cancers
  • Treatment of such conditions can be carried out with a variety of reagents, such as, for example, anti- cytokine antibodies, anti-cytokine receptor antibodies, anti-endotoxin antibodies, bradykinin antagonists, synthetic peptide blocking bradykinin receptors, bactericidal/permeability increasing protein, antibodies to platelet activating factor, inhibitors of arachidonate metabolism, inhibitors of nitric oxide synthase enzymes, immunosuppressors, diabetic therapeutic agents, anti-infla matories, agents useful for stroke therapy, agents useful for asthma therapy, agents useful for cirrhosis therapy, anti-cancer therapeutics, anti-microbial therapeutics, anti-fungal therapeutics, anti-retroviral therapeutics, agents useful for the treatment of opportunistic infections and malignancies, agents useful for the treatment of Lupus erythmatosus, agents useful for the treatment of uveitis, thrombolytic agents, antispasmodic agents, antidiarrheal agents
  • Such agents employed either alone or as part of a combination of any two or more thereof, can advantageously be combined with dithiocarbamate-containing nitric oxide scavengers as described herein, and can be used for a variety of indications, such as for example, anti-endotoxin therapy (e.g., antibodies to endotoxin, antibodies to LPS-binding protein, soluble CD14 protein, bactericidal/permeability increasing protein, polymyxin B, and the like) , inhibition of cytokine synthesis/release (e.g., employing phosphodiesterase inhibitors,
  • anti-endotoxin therapy e.g., antibodies to endotoxin, antibodies to LPS-binding protein, soluble CD14 protein, bactericidal/permeability increasing protein, polymyxin B, and the like
  • inhibition of cytokine synthesis/release e.g., employing phosphodiesterase inhibitors
  • anti-cytokine therapy e.g., employing antibodies to TNF, soluble TNF receptors, IL-1 receptor antagonists, antibodies to IL-1 receptors, antibodies to IL-6, antibodies to interferon- ⁇ , soluble interferon- ⁇ receptors, and the like
  • anti-cytokine therapy e.g., employing antibodies to TNF, soluble TNF receptors, IL-1 receptor antagonists, antibodies to IL-1 receptors, antibodies to IL-6, antibodies to interferon- ⁇ , soluble interferon- ⁇ receptors, and the like
  • inhibition of the coagulation cascade and of complement activation, employing such agents as anti-Factor XII antibodies, antibodies to C5a, Cl-esterase inhibitors, soluble Crl, and the like
  • PAF platelet activating factor
  • arachidonate metabolism e.g., employing agents such as cyclooxygenase inhibitors, lipoxygenase inhibitors, leukotriene inhibitors, thromboxane A 2
  • arginine analogs such as L-N G -methylarginine , L-N G -nitroarginine,
  • 2-phenylimidazole, and the like calmodulin antagonists (such as chlorpro azine, W-7, and the like) , and the like) ; immunosuppression (e.g., employing one or more agents such as cyclosporin A, OKT3, FK506, mycophenolate mofetil (MMF) , azathioprine, corticosteroids (such as prednisone) , antilymphocyte globulin, antithymocyte globulin, and the like) , diabetic therapy (e.g.
  • immunosuppression e.g., employing one or more agents such as cyclosporin A, OKT3, FK506, mycophenolate mofetil (MMF) , azathioprine, corticosteroids (such as prednisone) , antilymphocyte globulin, antithymocyte globulin, and the like
  • diabetic therapy e.g.
  • agents such as free pancreatic islets, encapsulated pancreatic islets, oral insulin, intravenous insulin, amylin hormone, and the like) , dihydropyridine calcium channel blockers (e.g., employing agents such as nifedipine, nitrendipine, nisoldipine, and the like) , acetohexamide, chlorpropamide, glyburide, glipizide, metformin, tolbutamide, tolazamide, and the like, inflammatory disease therapy (e.g., employing disease-modifying agents (such as antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metronidazole, injectable and oral gold,
  • disease-modifying agents such as antimalarials, methotrexate, sulfasalazine, mesalamine, azathioprine, 6-mercaptopurine, metroni
  • D-penicillamine, and the like corticosteroids, non - s t er o i da 1 antiinflammatory drugs (such as acetominophen, aspirin, sodium salicylate, magnesium salicylate, choline magnesium salicylate, salicylsalicylic acid, ibuprofen, naproxen, diclofenac, diflunisal, etodolac, fenoprofen calcium, fluriprofen, piroxicam, indomethacin, ketoprofen, ketorolac tromethamine, meclofenamate, meclofenamate sodium, mefenamic acid, nabumetone, oxaprozin, phenyl butyl nitrone
  • non s t er o i da 1 antiinflammatory drugs such as acetominophen, aspirin, sodium salicylate, magnesium salicylate, choline magnesium salicylate, salicylsalicylic acid, i
  • stroke therapy e.g., employing one or more agents such as fibrinolytic agents (such as streptokinase, acylated plasminogen- streptokinase complex, urokinase, tissue plasminogen activator, and the like) , employing monoclonal antibodies directed against leukocyte adhesion molecules (such as intercellular adhesion molecule-1
  • IMM-1 vascular endothelial growth factor
  • CD18 transforming growth factor-beta 1
  • glutamate antagonists such as lamotrigine, dizolcilpine maleate (MK 801), BW619C89, BW1003C87, and the like
  • NMDA antagonists such as CGS 19755 (Selfotel) , aptiganel hydrochloride, dextrorphar, d-CPPene, and the like
  • GABA agonists such as muscimol
  • free radical scavengers such as allopurinol
  • asthma therapy e.g., employing bronchodilators (such as albuterol, salmeterol, metaproternol, bitolterol, pirbuterol, terbutaline, isoproterenol, epinephrine, and the like) , theophyllines (such as theophylline, aminophylline, and the like), corticosteroids (such as beclomethasone, prednisone, and the like) , antimediators
  • bronchodilators such as albuterol, salmeterol, metaproternol, bitolterol, pirbuterol, terbutaline, isoproterenol, epinephrine, and the like
  • theophyllines such as theophylline, aminophylline, and the like
  • corticosteroids such as beclomethasone, prednisone, and the like
  • cirrhosis therapy e.g., employing diuretics (such as spironolactone) , opiate antagonists
  • anti-cancer therapy e.g., employing one or more agents such as alkylating agents (such as mechlorethamine, chlorambuccil, ifosfamide, melphalan, busulfan, carmustine, lomustine, procarbazine, dacarbazine, cisplatin, carboplatin, and the like) , anti etabolites
  • hormonal agents such as testosterone propionate, fluoxymesterone, flutamide, diethylstilbestrol, ethinyl estradiol, tamoxifen, hydroxyprogesterone caproate, medroxyprogesterone, megestrol acetate , and the l i ke )
  • adrenocorticosteroids such as prednisone
  • aromatase inhibitors such as amino glutethimide
  • leuprolide such as interferon- ⁇ 2a, interferon- ⁇ 2b, interleukin-2, and the like
  • peptide hormone inhibitors such as octreotide acetate
  • natural products such as vinblastine, vincristine, vinorelbine
  • agents such as celftriaxone, TMP-SMZ, penicillin, aminoglycosides, vancomycin, gentamicin, rifampin, imipenem, clindamycin, metronidazole, tetracycline, erythromycin, sulfonamide, streptomycin, ampicillin, isoniazid, pyrazinamide, ethambutol, and the like
  • anti-fungal therapy e.g., employing agents such as amphotericin B, griseofulvin, myastatin, flucytosine, natamycin, antifungal imidazoles (e.g.
  • anti-retroviral therapy e.g., employing agents such as protease inhibitors (such as
  • opportunistic infections and malignancies e.g., anti-AIDS treatment, employing agents such as pentamidine, trimethoprim/sulfamethoxazole, primaquine, atovaquone, clarithromycin, clofazimine, ethambutol, rifampin, amikacin, ciprofloxacin, pyrimethamine, amphotericin B, ganciclovir, foscarnet, fluconazole, ketoconazole, acyclovir, and the like) ,
  • anti-AIDS treatment employing agents such as pentamidine, trimethoprim/sulfamethoxazole, primaquine, atovaquone, clarithromycin, clofazimine, ethambutol, rifampin, amikacin, ciprofloxacin, pyrimethamine, amphotericin B, ganciclovir, foscarnet, fluconazole, keto
  • Lupus erythymatosus therapy e.g., employing agents such as hydroxychloroquine sulfate, chloroquine sulfate, quinacrine, dapsone, isotretinoin, and the like
  • uveitis therapy e.g., employing agents such as corticosteroids, azathioprine, cyclosporine, and the like
  • thrombolytic therapy for acute myocardial infarction e.g. , employing agents such as streptokinase, tissue plasminogen activator
  • antispasmodic treatment e.g., employing agents such as dicyclomine, hyoscyamine, propantheline, and the like
  • antidiarrheal treatment e.g., employing agents such as loperamide, diphenoxylate with atropine, and the like
  • anticonstipation treatment e.g., employing agents such as fiber supplementation with bran, psyllium, methylcellulose, polycarbophil, cisapride, and the like
  • antihistamine therapy e.g., employing agents such as ethanolamines (such as diphenhydramine, clemastine, and the like) , ethylenediamines (such as brompheniramine, chlorpheniramine, triprolidine, and the like)
  • phenothiazines such as hydroxyzine
  • piperidines such as terfenadine, astemizole
  • Presently preferred indications for treatment in accordance with the present invention include septic shock, ischemia, ulcers, ulcerative colitis, diabetes, arthritis, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, cirrhosis or allograft rejection, and the like.
  • the dithiocarbamate-containing nitric oxide scavenger is administered in combination with one or more of the above-described agents, optionally including an antibiotic (e.g., gentamicin, tobramycin, amikacin, piperacillin, clindamycin, cefoxitin or vancomycin, or mixtures thereof), a vasoactive agent (e.g., a catecholamine, noradrenaline, dopamine or dobutamine) , or mixtures thereof.
  • an antibiotic e.g., gentamicin, tobramycin, amikacin, piperacillin, clindamycin, cefoxitin or vancomycin, or mixtures thereof
  • a vasoactive agent e.g., a catecholamine, noradrenaline, dopamine or dobutamine
  • nitric oxide scavengers can be delivered in a variety of ways, such as, for example, orally, intravenously, subcutaneously, parenterally, rectally, by inhalation, and the like. Since individual subjects may present a wide variation in severity of symptoms and each drug has its unique therapeutic characteristics, the precise mode of administration, dosage employed and treatment protocol for each subject is left to the discretion of the practitioner.
  • physiologically active composition(s) comprising an "agent” and a compound having the structure I, as described above, in a suitable vehicle rendering said compound amenable to oral delivery, transdermal delivery, intravenous delivery, intramuscular delivery, topical delivery, nasal delivery, and the like.
  • compositions can be delivered in a variety of pharmaceutically acceptable forms.
  • the above-described compositions can be delivered in the form of a solid, solution, emulsion, dispersion, micelle, liposome, and the like.
  • compositions of the present invention can be used in the form of a solid, a solution, an emulsion, a dispersion, a micelle, a liposome, and the like, wherein the resulting composition contains one or more each of the scavenging and inhibiting compounds contemplated for use in the practice of the present invention, as active ingredients thereof, in admixture with an organic or inorganic carrier or excipient suitable for enteral or parenteral applications.
  • the active ingredients may be compounded, for example, with the usual non-toxic, pharmaceutically acceptable carriers for tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use.
  • the carriers which can be used include glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, 23 medium chain length triglycerides, dextrans, and other carriers suitable for use in manufacturing preparations, in solid, semisolid, or liquid form.
  • auxiliary, stabilizing, thickening and coloring agents and perfumes may be used.
  • the active compounds i.e., "agents” and compounds of structure I as described herein
  • compositions containing the active ingredients contemplated herein may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions.
  • such compositions may contain one or more agents selected from a sweetening agent (such as sucrose, lactose, or saccharin) , flavoring agents (such as peppermint, oil of wintergreen or cherry) , coloring agents and preserving agents, and the like, in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets containing the active ingredients in admixture with non-toxic pharmaceutically acceptable excipients may also be manufactured by known methods.
  • the excipients used may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, and the like; (2) granulating and disintegrating agents such as corn starch, potato starch, alginic acid, and the like; (3) binding agents such as gum tragacanth, corn starch, gelatin, acacia, and the like; and (4) lubricating agents such as magnesium stearate, stearic acid, talc, and the like.
  • inert diluents such as calcium carbonate, lactose, calcium phosphate, sodium phosphate, and the like
  • granulating and disintegrating agents such as corn starch, potato starch, alginic acid, and the like
  • binding agents such as gum tragacanth, corn starch, gelatin, aca
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract, thereby providing sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in the U.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tablets for controlled release.
  • formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate, kaolin, or the like. They may also be in the form of soft gelatin capsules wherein the active ingredients are mixed with water or an oil medium, for example, peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate, kaolin, or the like.
  • water or an oil medium for example, peanut oil, liquid paraffin, or olive oil.
  • the pharmaceutical compositions may be in the form of a sterile injectable suspension.
  • This suspension may be formulated according to known methods using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides, fatty acids (including oleic acid) , naturally occurring vegetable oils like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or synthetic fatty vehicles like ethyl oleate or the like. Buffers, preservatives, antioxidants, and the like can be incorporated as required.
  • compositions contemplated for use in the practice of the present invention may also be administered in the form of suppositories for rectal administration of the active ingredients.
  • These compositions may be prepared by mixing the active ingredients with a suitable non- irritating excipient, such as cocoa butter, synthetic glyceride esters of polyethylene glycols (which are solid at ordinary temperatures, but liquify and/or dissolve in the rectal cavity to release the active ingredients) , and the like.
  • Typical daily doses of dithiocarbamate-containing nitric oxide scanvengers lie within the range of from about 10 ⁇ g up to about 100 mg per kg body weight, and, preferably within the range of from 50 ⁇ g to 10 mg per kg body weight and can be administered up to four times daily.
  • the daily IV dose lies within the range of from about 1 ⁇ g to about 100 mg per kg body weight, and, preferably, within the range of from 10 ⁇ g to 10 mg per kg body weight.
  • the dosage of dithiocarbamate- containing nitric oxide scavenger employed in the practice of the present invention falls in the range of about 0.01 mmoles/kg body weight of the subject/hour up to about 0.5 mmoles/kg/hr.
  • Wistar rats male, 230-300 g were supplied by Simonson Laboratories (Gilroy, CA) .
  • Lipopolysaccharide LPS; S. typhosa, endotoxin was obtained from Sigma (St. Louis, MO) .
  • N.-Methyl-D-glucamine and carbon disulfide were obtained from Aldrich (Milwaukee, WI) .
  • N.-Methyl-D- glucamine dithiocarbamate (MGD) was synthesized by following the method of Shinobu et al. (Acta Pharmacol.
  • one [(MGD) 2 /Fe] complex binds to one molecule of nitric oxide to form a [(MGD) 2 /Fe- NO] complex.
  • free nitric oxide is a potent vasodilator, nitric oxide bound to [(MGD) 2 /Fe] is not.
  • the resulting complex is then excreted from the body in the urine, thereby reducing in vivo nitric oxide levels.
  • [(MGD) 2 /Fe] i s potentially useful for the treatment of systemic hypotension (extreme drop in blood pressure) , caused by abnormally elevated levels of nitric oxide; a condition which has been associated with many inflammatory and infectious diseases.
  • [(MGD) 2 /Fe] has been shown to be safe inasmuch as the animals survived after injections of up to 1% of their body weight without apparent side effects (Lai and Komarov, supra) .
  • MAP mean arterial pressure
  • [(MGD) 2 /Fe] (2/0.4) is defined as the ratio of [(MGD) 2 /Fe] to be 2-to-0.4.
  • the MAP of anesthetized rats was in the range of 96 to 99 mmHg. Two hours after LPS treatment, the MAP decreased to between 71 and 77 mmHg, which is indicative of the onset of systemic hypotension, caused by abnormally elevated levels of nitric oxide, as also shown in Figure 1. While the 2.0 hr saline infusion did not change the MAP, infusions of [(MGD) 2 /Fe] complex at various ratios, ranging from 2-to-0.4 (MGD to Fe) to 2-to-0 (MGD to Fe) , restored the blood pressure to 89-95 mmHg (Table 1) . These results suggest that the i.v. infusion of MGD either with or without added iron (Fe) , can restore blood pressure in hypotensive rats induced by LPS challenge (Table 1) .
  • MGD does not bind -NO
  • the restoration of the MAP by MGD infusion may be attributed to the MGD chelation of cellular iron released by excess -NO production, which is known to attack cellular iron-containing proteins and result in cellular iron loss during sepsis or septic shock (see, for example, Kim et al., in J. Biol. Chem. 270:5710-5713 (1995)).
  • dithiocarbamate- containing nitric oxide scavengers such as MGD, either with or without added iron, are effective for the treatment of systemic hypotension, a condition which is associated with many inflammatory and/or infectious diseases.
  • Wistar rats are anesthetized with Ketamine/Xylazine (55 mg/kg plus 5.5 mg/kg) .
  • a catheter is implanted in the femoral vein for drug administration.
  • the femoral artery is cannulated for continuous blood pressure measurement.
  • the animals are allowed to recover from surgery for a period of 3 days prior to experimentation.
  • the conscious rats are retained in restrainers and the artery line is connected to the pressure transducer for recording.
  • Rats are injected with an i.v. bolus dose of LPS (S. Typhosa, endotoxin, 10-20 mg/kg) .
  • LPS LPS
  • rats Two hours after LPS challenge, rats are then subjected to one of the following treatments (8 animals in each group) :
  • the infusion of anti-TNF antibodies at two hours after LPS challenge as indicated in group 3 may not be able to block the induction of the inducible nitric oxide synthase gene, which results in the production of iNOS, resulting in the overproduction of nitric oxide.
  • group 4 the co-infusion of anti-TNF antibodies and [(MGD) 2 /Fe] is expected to produce a similar survival rate as that for group 2, employing [(MGD) 2 /Fe] infusion alone.

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Abstract

Cette invention se rapporte à des procédés thérapeutiques combinatoires pour l'inactivation ou l'inhibition in vivo de la formation (soit directement soit indirectement) d'espèces qui induisent l'expression de la monoxyde d'azote synthétase, ainsi que la réduction des niveaux de monoxyde d'azote produits à la suite de l'expression de .NO synthétase. A la différence de l'approche par inhibition de l'état actuel de la technique (où la fonction des enzymes responsables de la production du monoxyde d'azote est inhibée), cette invention utilise une combinaison de l'approche par inactivation (ou inhibition) et par piégeage, où le stimulus de l'expression de la monoxyde d'azote synthétase est inactivé, ou sa production est inhibée, et le monoxyde d'azote produit en excédent est fixé in vivo à un piégeur de monoxyde d'azote approprié. Les complexes qui en résultent rendent inactif le stimulus de l'expression de la monoxyde d'azote synthétase (ou inhibent sa production) et rendent inoffensif le monoxyde d'azote. Ces complexes finissent par être excrétés dans l'urine de l'organisme hôte. Dans un autre de ses aspects, cette invention se rapporte à la réduction des niveaux de monoxyde d'azote élevés associés à des états infectieux et/ou inflammatoires (et au traitement de ces états), grâce à l'utilisation d'un procédé thérapeutique combinatoire dans lequel un agent pour le traitement de ces états infectieux et/ou inflammatoires est administré conjointement à un composé de dithiocarbamate comme piégeur du monoxyde d'azote produit en excédent. Cette invention se rapporte en outre à des compositions et à des formulations utiles pour réaliser les procédés décrits ci-dessus.
PCT/US1997/004131 1996-03-05 1997-03-05 Procedes therapeutiques combinatoires utilisant des piegeurs de monoxyde d'azote et compositions utiles dans ces procedes WO1997032585A1 (fr)

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835659A1 (fr) * 1996-10-14 1998-04-15 Hoechst Marion Roussel Deutschland GmbH Utilisation d'antagonistes non peptidiques de la bradykinine dans la préparation de médicaments pour le traitement et la prévention de la maladie d'Alzheimer
WO1999062887A1 (fr) * 1998-06-01 1999-12-09 Shionogi & Co., Ltd. Derives de cyanoiminoquinoxaline
WO1999051215A3 (fr) * 1998-04-06 2000-03-09 Fujisawa Pharmaceutical Co Nouvelle utilisation
US6093743A (en) * 1998-06-23 2000-07-25 Medinox Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor
WO2000048591A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Combinaisons pour traiter les maladies faisant intervenir l'angiogenese
US6265420B1 (en) 1998-06-23 2001-07-24 Medinox, Inc. Use of nitric oxide scavengers to treat side effects caused by therapeutic administration of sources of nitric oxide
US6274627B1 (en) 1999-10-12 2001-08-14 Medinox, Inc. Conjugates of dithiocarbamate disulfides with pharmacologically active agents and uses therefor
WO2000061126A3 (fr) * 1999-04-09 2001-08-23 Lilly Co Eli Methode de traitement de troubles neurologiques
EP1157705A2 (fr) * 2000-04-28 2001-11-28 Pfizer Products Inc. Utilisation d'un inhibiteur de la phosphodiestérase dans la fabrication d'un médicament destiné à la stabilisation de la pression sanguine lors de l'hémodialyse
US6596770B2 (en) 2000-05-05 2003-07-22 Medinox, Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor
WO2004004754A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles combinaisons medicamenteuses a base de sels de magnesium et d'agents fibrinolytiques
WO2004019921A2 (fr) * 2002-08-29 2004-03-11 University Of Southampton Traitement de maladies hepatiques
WO2008038302A2 (fr) * 2006-09-26 2008-04-03 Jegannathan Srinivas Formulation thérapeutique comprenant une sulfonylurée, un biguanide, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique
US8101371B2 (en) 2007-10-18 2012-01-24 Musc Foundation For Research Development Methods for the diagnosis of genitourinary cancer

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4686100A (en) * 1985-04-02 1987-08-11 The Board Of Trustees Of The Leland Stanford Junior University Method for the treatment of adult respiratory distress syndrome
US5137889A (en) * 1983-12-02 1992-08-11 Otsuka Pharmaceutical Co., Ltd. Dihydropyridine derivatives and process for preparing the same
US5176908A (en) * 1988-12-19 1993-01-05 American Cyanamid Company Method for the treatment of endotoxic shock in mammal
US5294430A (en) * 1988-09-12 1994-03-15 University Of Rochester Use of dithiocarbamates to treat myelosuppression
US5317040A (en) * 1993-01-26 1994-05-31 Washington University Method for the treatment of pertussis with aminoguanidine
US5411952A (en) * 1987-09-03 1995-05-02 University Of Georgia Research Foundation, Inc. Ocular cyclosporine composition
US5426046A (en) * 1983-11-08 1995-06-20 The Board Of Trustees Of The Leland Stanford Junior University Human monoclonal antibody to lipid A of gram negative bacteria
US5436265A (en) * 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof
US5460954A (en) * 1992-04-01 1995-10-24 Cheil Foods & Chemicals, Inc. Production of human proinsulin using a novel vector system
US5461058A (en) * 1989-06-06 1995-10-24 Calne; Roy Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
US5530141A (en) * 1992-03-04 1996-06-25 Center For Innovative Technology 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5426046A (en) * 1983-11-08 1995-06-20 The Board Of Trustees Of The Leland Stanford Junior University Human monoclonal antibody to lipid A of gram negative bacteria
US5137889A (en) * 1983-12-02 1992-08-11 Otsuka Pharmaceutical Co., Ltd. Dihydropyridine derivatives and process for preparing the same
US4686100A (en) * 1985-04-02 1987-08-11 The Board Of Trustees Of The Leland Stanford Junior University Method for the treatment of adult respiratory distress syndrome
US5411952A (en) * 1987-09-03 1995-05-02 University Of Georgia Research Foundation, Inc. Ocular cyclosporine composition
US5294430A (en) * 1988-09-12 1994-03-15 University Of Rochester Use of dithiocarbamates to treat myelosuppression
US5176908A (en) * 1988-12-19 1993-01-05 American Cyanamid Company Method for the treatment of endotoxic shock in mammal
US5461058A (en) * 1989-06-06 1995-10-24 Calne; Roy Methods of inhibiting transplant rejection in mammals using rapamycin and derivatives and prodrugs thereof
US5530141A (en) * 1992-03-04 1996-06-25 Center For Innovative Technology 2,4-diaryl-1,3-dithiolanes; 2,4-diaryl-1,3-dioxolanes; 2,4-diaryl-1,3-oxathiolanes; and 2,5-diaryl-1,3-oxathiolanes for the treatment of disorders mediated by platelet activating factor or products of 5-lipoxygenase
US5460954A (en) * 1992-04-01 1995-10-24 Cheil Foods & Chemicals, Inc. Production of human proinsulin using a novel vector system
US5449687A (en) * 1992-04-02 1995-09-12 Smithkline Beecham Corporation 4-phenyl-1,2-cyclohexyl derivatives and anti-inflammatory compositions and methods thereof
US5317040A (en) * 1993-01-26 1994-05-31 Washington University Method for the treatment of pertussis with aminoguanidine
US5436265A (en) * 1993-11-12 1995-07-25 Merck Frosst Canada, Inc. 1-aroyl-3-indolyl alkanoic acids and derivatives thereof useful as anti-inflammatory agents

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
J. INTERFER. CYTOKIN. RES., 1995, Vol. 15, DEGUCHI et al., "Exogenous and Endogenous Type I Interferons Inhibit Interferon-Gamma-Induced Nitric Oxide Production and Nitric Oxide Synthase Expression in Murine Peritoneal Macrophages", pages 977-984. *

Cited By (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0835659A1 (fr) * 1996-10-14 1998-04-15 Hoechst Marion Roussel Deutschland GmbH Utilisation d'antagonistes non peptidiques de la bradykinine dans la préparation de médicaments pour le traitement et la prévention de la maladie d'Alzheimer
US5952346A (en) * 1996-10-14 1999-09-14 Hoechst Marion Roussel Deutschland Gmbh Use of non-peptide bradykinin antagonists for the treatment or prevention of Alzheimer's disease
WO1999051215A3 (fr) * 1998-04-06 2000-03-09 Fujisawa Pharmaceutical Co Nouvelle utilisation
WO1999062887A1 (fr) * 1998-06-01 1999-12-09 Shionogi & Co., Ltd. Derives de cyanoiminoquinoxaline
US6525054B1 (en) 1998-06-01 2003-02-25 Shionogi & Co., Ltd. Cyanoiminoquinoxaline derivatives
EP1089723A1 (fr) * 1998-06-23 2001-04-11 Medinox, Inc. Methodes therapeutiques utilisant des derives de bisulfure de dithiocarbamates et compositions utilisees
EP1089723A4 (fr) * 1998-06-23 2003-07-16 Medinox Inc Methodes therapeutiques utilisant des derives de bisulfure de dithiocarbamates et compositions utilisees
US6265420B1 (en) 1998-06-23 2001-07-24 Medinox, Inc. Use of nitric oxide scavengers to treat side effects caused by therapeutic administration of sources of nitric oxide
US6589991B1 (en) 1998-06-23 2003-07-08 Medinox, Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor
US6093743A (en) * 1998-06-23 2000-07-25 Medinox Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor
US6316502B1 (en) 1998-06-23 2001-11-13 Medinox, Inc. Therapeutic methods employing disulfide derivatives of dithiocarbonates and compositions useful therefor
US7087627B1 (en) 1999-02-16 2006-08-08 Angiogene Pharmaceuticals Ltd. Combinations for the treatment of diseases involving angiogenesis
WO2000048591A1 (fr) * 1999-02-16 2000-08-24 Angiogene Pharmaceuticals Ltd. Combinaisons pour traiter les maladies faisant intervenir l'angiogenese
WO2000061126A3 (fr) * 1999-04-09 2001-08-23 Lilly Co Eli Methode de traitement de troubles neurologiques
US6274627B1 (en) 1999-10-12 2001-08-14 Medinox, Inc. Conjugates of dithiocarbamate disulfides with pharmacologically active agents and uses therefor
EP1157705A3 (fr) * 2000-04-28 2003-09-10 Pfizer Products Inc. Utilisation d'un inhibiteur de la phosphodiestérase dans la fabrication d'un médicament destiné à la stabilisation de la pression sanguine lors de l'hémodialyse
EP1157705A2 (fr) * 2000-04-28 2001-11-28 Pfizer Products Inc. Utilisation d'un inhibiteur de la phosphodiestérase dans la fabrication d'un médicament destiné à la stabilisation de la pression sanguine lors de l'hémodialyse
US6596770B2 (en) 2000-05-05 2003-07-22 Medinox, Inc. Therapeutic methods employing disulfide derivatives of dithiocarbamates and compositions useful therefor
WO2004004754A1 (fr) * 2002-07-09 2004-01-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles combinaisons medicamenteuses a base de sels de magnesium et d'agents fibrinolytiques
WO2004019921A2 (fr) * 2002-08-29 2004-03-11 University Of Southampton Traitement de maladies hepatiques
WO2004019921A3 (fr) * 2002-08-29 2004-09-23 Univ Southampton Traitement de maladies hepatiques
WO2008038302A2 (fr) * 2006-09-26 2008-04-03 Jegannathan Srinivas Formulation thérapeutique comprenant une sulfonylurée, un biguanide, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique
WO2008038302A3 (fr) * 2006-09-26 2008-05-29 Jegannathan Srinivas Formulation thérapeutique comprenant une sulfonylurée, un biguanide, et une fraction libérant de l'oxyde nitrique qui est complexée avec un capteur de l'oxyde nitrique
US8101371B2 (en) 2007-10-18 2012-01-24 Musc Foundation For Research Development Methods for the diagnosis of genitourinary cancer

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