+

WO1994016740A1 - Utilisation de composes d'apport d'oxyde nitrique pour le traitement ou la prevention des problemes dus a une cirrhose alcoolique du foie - Google Patents

Utilisation de composes d'apport d'oxyde nitrique pour le traitement ou la prevention des problemes dus a une cirrhose alcoolique du foie Download PDF

Info

Publication number
WO1994016740A1
WO1994016740A1 PCT/US1994/000970 US9400970W WO9416740A1 WO 1994016740 A1 WO1994016740 A1 WO 1994016740A1 US 9400970 W US9400970 W US 9400970W WO 9416740 A1 WO9416740 A1 WO 9416740A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitroso
arginine
liver disease
nitric oxide
individual
Prior art date
Application number
PCT/US1994/000970
Other languages
English (en)
Inventor
Amin Nanji
Jonathan Stamler
Joseph Loscalzo
Original Assignee
Brigham And Women's Hospital
New England Deaconess Hospital
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Brigham And Women's Hospital, New England Deaconess Hospital filed Critical Brigham And Women's Hospital
Priority to AU62327/94A priority Critical patent/AU6232794A/en
Publication of WO1994016740A1 publication Critical patent/WO1994016740A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A61K38/063—Glutathione
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/28—Compounds containing heavy metals
    • A61K31/295—Iron group metal compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K38/38—Albumins

Definitions

  • Nitric Oxide-Delivering Compounds for The Treatment Or Prevention Of Alcoholic
  • the invention relates to the use of nitric oxide-delivering compounds for the treatment or prevention of liver disease induced' by alcohol or other hepatotoxins.
  • liver acts as a filter to clear potentially toxic endogenous and exogenous compounds from circulation, and facilitates the extraction and metabolism of substances originating in the digestive tract and entering the portal circulation.
  • Adequate liver function requires the continuous movement of molecules between hepatocytes and the blood stream; thus, a properly functioning vascular system is essential for optimal exchange efficiency.
  • Chronic exposure to alcohol leads to numerous metabolic and structural alterations within the liver which result in injury and consequential impairment of liver function.
  • alcoholic liver injury is very similar to ischemic heart disease (Thurman et al., Fund. Appl. Toxocol., 4: 1250 (1984)).
  • arginine has an important role in all vascular systems because it serves as the substrate for the synthesis of nitric oxide by vascular endothelial cells (Palmer et al. , Nature 55:664-666 (1988a)). Synthesis of nitric oxide by the arginine pathway accounts for the endogenous vasodilatory action of endothelium-derived relaxing factor (EDRF).
  • EDRF endothelium-derived relaxing factor
  • nitric oxide In addition to its significant role as an endogenous vasodilator, nitric oxide exerts cytostatic and cytotoxic actions against microbes and tumor cells, and prevents free radical-mediated injury, thrombocyte adherence and platelet aggregation. In experimental studies, hepatocytes subjected to chronic ethanol exposure exhibited a decreased capacity to produce nitric oxide, suggesting that nitric oxide deficiency is implicated in liver damage associated with alcohol ingestion (Silvio et al.. Gastroenterology 102(4 part 2):A801 (May 1992)).
  • liver injury which is also characterized by arginine deficiency, vascular distortion, liver hypoxia, and the potential to progress to cirrhosis.
  • thioacetamide a well known hepatotoxin
  • Other chemical compounds such as carbon tetrachloride, are associated with an increase in orotic acid excretion, indicating a deficiency in arginine levels (Visek et al. , J. Amer. Coll. Nutrition 5: 123-166 (1986)).
  • liver injury and cirrhosis induced by alcohol and other hepatotoxins are serious illnesses which require long-term medical supervision and careful management.
  • therapy of underlying liver disease is largely supportive, with specific treatment being directed to the particular complications.
  • the lack of adequate therapy for advanced stages of alcoholic liver injury emphasizes the need for pharmaceutical agents which are more efficacious in treating advanced liver injury, and are also suitable for prophylaxis and early treatment during the fully reversible initial stages of diseases.
  • pharmacological agents which can act directly to prevent or reverse liver injury resulting from nitric oxide deficiency.
  • liver injury induced by alcohol and other hepatotoxins has been associated with the deficiency of nitric oxide, and it has been proposed that this deficiency plays a causal role in the pathogenesis of liver injury. Consequently, the inventors have conceived of a method for preventing or treating liver injury, comprising the administration of a nitric oxide-delivering compound to a patient in need of such treatment.
  • the invention relates to a method for the treatment of liver disease, comprising administration of a therapeutical ly effective amount of nitric oxide-delivering compound to an individual afflicted with said liver disease.
  • the invention also relates to a method for the prevention of liver disease, comprising the administration of a therapeutically effective amount of a nitric oxide-delivering compound to an individual at risk for acquiring said liver disease.
  • Liver disease may be induced by alcohol ingestion or exposure of said individual to compounds other than alcohol which are hepatotoxic, such as a pharmacologic agent or industrial toxin.
  • the nitric oxide-delivering compound which is administered in the methods of the invention comprises an S-nitrosothiol, S-nitroso-protein, thionitrate, thionitrite, sydnonimine, furoxan, organic nitrate, nitroprusside, nitroglycerine, iron-nitrosyl compound, or other related compound.
  • Particular S-nitrosothiol compounds include S-nitroso-N-acetylcysteine, S-nitroso- cysteine, S-nitroso-homocysteine, S-nitroso-captopril, S-nitroso-glutathione, S- nitroso-pantathoine derivatives, S-nitroso-penicillamine, long-chain lipophilic nitrosothiols and S-nitroso-dithiols.
  • Particular S-nitroso-proteins include S- nitroso-albumin.
  • the above methods also include administration of the nitric oxide- delivering compound as part of a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers.
  • Said pharmaceutical composition is administered to an individual by a route comprising intravenous, intramuscular, subcutaneous, oral, topical, rectal, intranasal or aerosol delivery.
  • the invention also relates to a method for preventing alcohol-induced liver disease in an individual comprising administering to the individual, a therapeutically effective amount of a nitric-oxide delivering compound in combination with an alcohol-containing beverage.
  • the invention further relates to a composition comprising an alcohol-containing beverage in combination with a therapeutically effective amount of a nitric oxide-delivering compound.
  • the invention also relates to a method for preventing alcohol-induced liver disease in an individual, comprising administering to an individual, a therapeutically effective amount of arginine or an arginine analog in combination with an alcohol-containing beverage.
  • the invention further relates to a composition comprising an alcohol-containing beverage in combination with a therapeutically effective amount of arginine or an arginine analog.
  • the arginine analog is selected from the group comprising arginine hydrochloride, N- ⁇ -benzoyl-L-arginine, N- ⁇ -benzoyl-L-arginine ethyl ester, L-citrulline, L-arginine methyl ester, D-phenylalanyl-L-propyl-L-arginine, N- ⁇ -benzoyl-L-arginine-ethylesterhydrochloride,poly-L-argininehydrochloride, NG-L-hydroxyarginine, arginine aspartate, N-omega-hydroxy-L-arginine.
  • Figure 1 shows the liver pathology score for groups of animals fed a diet of either saturated fat plus ethanol, or corn oil plus ethanol, for one, two, or four week time periods
  • Figure 2 shows the level of nitric oxide in non-parenchymal hepatic cells harvested from the livers of rats fed either saturated fat plus ethanol, or corn oil plus ethanol, over one, two, or four week time periods.
  • treatment is intended that the symptoms of the disease or pathological conditions which caused the disease be ameliorated or completely eliminated.
  • prevention is intended that the factor or factors which cause the disease be prevented.
  • liver disease any liver disorder which associated with decreased levels of plasma arginine or nitric oxide, and any impairment of liver function resulting therefrom, including impairment in the functioning of other bodily organs which occurs as the result of impaired liver function.
  • ⁇ Individual. By the term “individual” is intended any living creature including mammals, and for example, humans. Therapeutically effective. By the term “therapeutically effective” is intended an amount of the particular compound which when administered to an individual, is sufficient to treat or prevent the symptoms and/or factors which cause the liver disease.
  • Nitric oxide-delivering is intended any chemical compound capable of delivering in vivo, nitric oxide or an equivalent nitric oxide species in a biologically active form.
  • Alcohol By the term “alcohol” is intended ethanol prepared in a form for human consumption.
  • Pharmacologic agent is intended a chemical compound intended for use in medical therapy.
  • the invention is based on the discovery by the inventors, that the treatment or prevention of liver disease can be accomplished by the administration of compounds which deliver nitric oxide in vivo, in a biologically active form.
  • liver disease resulting from chronic ingestion of alcohol is associated with a decrease in nitric oxide levels in hepatic cells, and the decrease in nitric oxide has a significant causative role in the pathogenesis of liver injury.
  • the invention provides a method for the treatment or prevention of liver disease by administering a nitric oxide-delivering compound to an individual afflicted with, or at risk of acquiring, liver disease.
  • One embodiment of the invention relates to a method for treating liver disease by administering a therapeutically effective amount of a nitric oxide- delivering compound to an individual afflicted with liver disease. While the inventors do not want to be limited to a particular theory regarding the mechanism by which nitric oxide-delivering compounds treat liver disease, it is proposed that by delivering nitric-oxide in a bioactive form, these compounds eliminate the nitric oxide deficiency caused by depleted levels of arginine. Once delivered, the nitric oxide causes vasodilation of constricted hepatic vessels, thereby improving liver perfusion and reducing liver hypoxia. In addition, these compounds act to reverse the abnormal platelet aggregation and other effects of endothelial damage caused by nitric oxide deficiency.
  • nitric oxide-delivering compounds are administered to prevent the development of liver disease in an individual at risk for acquiring liver disease as a result of alcohol ingestion.
  • Administration of a nitric oxide-delivering compound to an individual at risk prevents nitric oxide deficiency, thereby preventing vasoconstriction, liver hypoxia, and other adverse consequences.
  • liver disease which is induced by any alcohol ingestion which is sufficiently prolonged or excessive so as to cause the ingesting individual to experience a deficiency in plasma levels of arginine or nitric oxide.
  • amount of alcohol required to induce these deficiencies will vary for each individual, depending on genetic predisposition, immune response, hormonal factors, environmental factors, nutrition, and other conditions which are associated with the alcohol ingestion.
  • Individuals afflicted with alcohol- induced liver disease may exhibit a variety of clinical manifestations, ranging from asymptomatic or mild illness, to fatal hepatic insufficiency.
  • plasma arginine and nitric oxide levels may be monitored using standard assay techniques which are routine to those in the art (Stamler et al. , Proc. Natl. Acad. Sci. USA, 89:444-448 (1992); Stamler et al , Proc. Natl. Acad. Sci. USA, 89:1614-1611 (1992); Stamler et al., Anal. Chan. 64:119- 785 (1992)).
  • Another embodiment of the invention relates to the administration of a therapeutically effective amount of a nitric oxide-delivering compound to an individual afflicted with liver disease or at risk of acquiring liver disease induced by exposure to a compound other than alcohol.
  • a nitric oxide-delivering compound include pharmacologic agents and industrial toxins which induce liver disease as a result of ingestion, inhalation, or topical or parenteral exposure.
  • liver disease examples include, but are not limited to, acetaminophen, methyldopa, methotrexate, isoniazid, halothane, chlorpromazine, sodium valproate, oral contraceptives, tetracycline, and erythromycin.
  • liver disease may be induced by the synergistic effect of exposure to a pharmacologic agent in conjunction with alcohol ingestion.
  • Industrial toxins are those chemical agents which are used primarily in industrial processes, but may also be used by individuals during such activities as paint stripping, painting, and automobile repairs.
  • industrial toxins include, but are not limited to lead, hexachlorobenzene, poiychlorinated biphenyls, toluene, methylene chloride, turpentine, petroleum distillate, carbon tetrachloride, trichlorethylene, and yellow phosphorus, and other petro-chemicals.
  • Nitric oxide-delivering compounds which are useful in the methods of the invention include, but are not limited to S-nitrosothiols, S-nitroso-proteins, nitroprusside, thionitrites, thionitrates, iron-nitrosyl compounds, sydnonimines, furoxans, nitrosonium salts, and organic nitrates, and related compounds.
  • S-nitrosothiols include, but are not limited to S-nitroso-N- acetylcysteine,S-nitroso-cysteine,S-nitroso-homocysteine,S-nitroso-captopril, S-nitroso-glutathione, S-nitroso-pantathoine derivatives, S-nitroso- penicillamine, long-chain lipophilic nitrosothiols, and S-nitroso-dithiols.
  • S-nitrosothiols are especially advantageous for use in the above methods of treatment or prevention of liver disease. These compounds have the capacity to deliver nitric oxide in a highly biologically relevant and non- toxic form, as nitrosonium or nitroxyl.
  • the inventors conducted studies to assess the reactivity of S-nitrosothiols in the presence of redox metals. The studies demonstrated that S-nitrosothiols were not reactive with redox metal, thus indicating that the reactive nitric oxide species donated by the S- nitrosothiol is nitrosonimun or nitroxyl.
  • the inventors have demonstrated that S-nitrosothiols increase the oxygen-binding capacity of hemoglobin, a globular protein, which binds reversibly to blood oxygen through passive diffusion from entry of air into the lungs. Hemoglobin-oxygen binding greatly increases the capacity of the blood to transport oxygen to bodily tissues. Therefore, the binding affinity between hemoglobin and oxygen is a critical factor in determining the level of oxygen transferred to the tissues, and in particular, the tissues of the liver. Studies conducted by the inventors demonstrated that the reaction between S-nitrosothiols and hemoglobin produced a leftward shift in the hemoglobin-oxygen association curve, indicating a significant increase in oxygen binding.
  • S-nitrosothiols further facilitates the treatment or prevention of liver hypoxia by increasing the oxygen-carrying capacity in the blood, and consequential oxygen transpo ⁇ to the liver.
  • Particular S-nitroso-proteins include, but are not limited to S-nitroso- albumin.
  • S-nitroso-proteins are particularly suitable for delivering nitric oxide in vivo.
  • a unique advantage of these compounds is that they have the capacity to deliver nitric oxide at a slower rate, thus providing sustaining and long- lasting vasodilation in clinical situations which require such an effect.
  • An additional advantage of these compounds is that they are much more easily assimilated physiologically because they are actually supplementing an already endogenous pool of bioactive nitric oxide.
  • S-nitroso-albumin is an especially suitable compound for the delivery of nitric oxide. As with other S-nitroso- proteins, this compound produces a less rapid, but much more persistent vasorelaxant response, which is advantageous in counteracting vasoconstriction resulting from liver disease, and also to promote sustained liver perfusion and oxygen delivery to hepatic tissue.
  • nitrosothiols are represented by the general formula CH 3 (CH ) x SNO.
  • S-nitroso-dithiols possess an additional thiol group, and are represented by the general formula HS(CH 2 ) x SNO.
  • Examples of sydnonimines include, but are not limited to SYN-1 and 3- morpholinosydnonimine.
  • Examples of organic nitrates include, but are not limited to, nitroglycerine, isosorbide dinitrate, erythritol tetranitrate and , pentaerythritol tetranitrate.
  • Iron-nitrosyl compounds are represented by the general formula X x Fe y (NO) z , wherein X is a low molecular weight or protein thiol, or a non-thiolate anion such as phosphate, ascorbate, anionic protein, or glycosaminoglycan, such as heparin sulfate.
  • An additional embodiment of the invention relates to the methods of the invention in which the nitric oxide-delivering compound is administered as part of a pharmaceutical composition, comprising a pharmaceutically acceptable carrier.
  • compositions utilized in this invention can be administered by intranasal, aerosol, oral, enteral, topical, sublingual, rectal, intramuscular, intravenous, or subcutaneous means.
  • the compounds of this invention can be employed in combination with conventional excipients; i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral or intranasal application which do not deleteriously react with the active compounds.
  • Suitable pharmaceutically acceptable carriers include, but are not limited to, water, salt solutions, alcohol, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, silicic acid, viscous paraffin, perfume oil, fatty acid monoglycerides and diglycerides, petroethral fatty acid esters, hydroxymethylcellulose, polyvinylpyrrolidone, etc.
  • the pharmaceutical preparations can be sterilized and if desired, mixed with auxiliary agents, e.g.
  • lubricants preferably oily or aqueous solutions, as well as suspensions, emulsions, or implants, including suppositories.
  • Ampules are convenient unit dosages.
  • tablets, dragees or capsules having talc and/or a carbohydrate carrier binder or the like, the carrier preferably being lactose and/or corn starch and/or potato starch.
  • a syrup, elixir or the like can be used wherein a sweetened vehicle is employed.
  • Sustained release compositions can be formulated including those wherein the active component is protected with differentially degradable coatings, e.g. , by microencapsulation, multiple coatings, etc.
  • active compounds used will vary according to the specific nitric oxide-delivering compound being utilized, the particular compositions formulated, the mode of application and the particular site of administration.
  • Optimal administration rates for a given protocol of administration can be readily ascertained by those skilled in the art, using conventional dosage determination tests conducted with regard to the foregoing guidelines.
  • a preferred dosage range is lnmol/kg/ minute to 1 mmol/kg/minute.
  • a "therapeutically effective amount" of a pharmaceutical composition is an amount which is sufficient to achieve the desired pharmacological effect.
  • the dosage required to provide an effective amount of the composition will vary, depending upon the age, health, physical condition, sex, weight and extent of disease, of the recipient. Additionally, the dosage may be determined by the frequency of treatment and the nature and scope of the desired effect. Appropriate dosages will be determined by those of ordinary skill in the art, using routine methods.
  • An additional embodiment of the invention relates to a method for preventing alcohol-induced liver disease by administering to an individual, a therapeutically effective amount of a nitric oxide-delivering compound in combination with an alcohol-containing beverage.
  • the invention also includes compositions comprising an alcohol-containing beverage in combination with a therapeutically effective amount of a nitric oxide-delivering compound.
  • Compounds which are to be added to alcoholic beverages may be prepared in the form of a liquid, gel or solid, such as a powder, granules, or a tablet.
  • the compounds may be combined with acceptable carriers, including water, salt solutions, alcohol, oils, preservatives, stabilizers, emulsifiers, buffers, colorings, flavorings and/or aromatic substances and the like which do not deleteriously react with the arginine compound.
  • Compounds may be suitable for addition to any ethanol-containing beverage which is prepared for human consumption.
  • Suitable ethanol-containing beverages include non- distilled spirits, such as beers, wines and hard ciders, and distilled spirits, such as various types of brandy, cognac, rum, vodka, gin, whisky, bourbon, vermouth or mixed drinks containing one or more non-distilled or distilled spirits.
  • the compounds may be suitable either for addition to the alcoholic beverage immediately prior to serving or prior to its packaging and storage.
  • Another embodiment of the invention relates to a method for preventing alcohol-induced liver disease in an individual, by administering to an individual, a therapeutically effective amount of arginine or an arginine analog in combination with an alcohol-containing beverage.
  • a preferred dosage range is 15-100 grams per day. While the inventors do not want to be limited to a particular mechanism of action, it is proposed that by providing arginine or an arginine analog which is a substrate for nitric oxide synthesis, nitric oxide deficiency will be prevented.
  • Another embodiment of the invention includes pharmaceutical compositions comprising an alcohol-containing beverage in combination with a therapeutically effective amount of arginine or an arginine analog.
  • arginine analogs include, but are not limited to, arginine hydrochloride, N- ⁇ -benzoyl-L-arginine, N- ⁇ -benzoyl-L-arginine ethyl ester, L-citrulline, L-arginine methyl ester, D-phenylalanyl-L-propyl-L-arginine, N- ⁇ -benzoyl-L-arginine-ethylesterhydrochloride,poly-L-argininehydrochloride, NG-L-hydroxyarginine, arginine aspartate, N-omega-hydroxy-L-arginine.
  • the total liver pathology score was calculated by adding the scores from each of the parameters.
  • NPC Non-parenchymal cells
  • NPC were harvested from the livers of anaesthetized rats using isolation procedures and buffers previously described (Nanji et al. , Gastroenterology 102:A510 (1992)). In all experimental groups, NPC from 4-5 rats were combined. This allowed the collection of an adequate amount of NPC for stimulation by lipopolysaccharide. Briefly, after intravenous administration of sodium heparin, the livers were exsanguinated by hepatic artery perfusion with Ca 2+ free buffer (0.01M HEPES with 0.39% NaCl - 0.05% KC1, Ph 7.4).
  • Livers were excised, minced and incubated with 0.05% collagenase in buffer (0.1M HEPES with 0.83% NaCL - 0.05 % Kcl - 0.05 M CaCU, Ph 7.6) at 37°C for 60 min. The resulting suspension was pelleted and reincubated with fresh collagenase buffer for 30 min. The cell suspension was pelleted and resuspended. Hepatocytes and cell clumps were removed by low speed centrifugation (500 g, 10 min. x 3). The remaining cells were washed with Gey's balanced salt solution. Final purification was achieved by centrifugation in a 17.5 % solution of metrizamide in Gey's balanced salt solution.
  • the sinusoidal cell preparation contains 60-65 % Kupffer cells following the gradient step; this is increased to 85-90% following adherence to plastic.
  • the yield of Kupffer cells is variable and depends on degree of fat infiltration, necrosis and inflammation.
  • no preparation was the content of hepatocytes greater than 1 %.
  • Two suspensions of 5X10 7 cells/ml in RPMI 1640 with 5% fetal bovine serum were placed in 35-cm 2 tissue culture dishes and incubated overnight at 37 °C. The next day, 200 ng/ml of lipopolysaccharide (E. coli J5 mutant of 0111B 4 serotype) was added to the cell suspensions. After 3 hours, the supernatants of cell suspensions were removed by centrifugation and stored at - 70°C for analysis of nitrites.
  • Nitrite (NO) was detected using previously described methods (Stamler et al. , Proc. Natl. Acad. Sci. USA, 89:1614-1611 (1992), Stamler et al. , Proc. Natl. Acad. Sci. USA, 89:444-448 (1992), and Stamler et al , Anal. Chem. 64:119-185 (1992), and Saville, Analyst 85:670-672 (1958)). As shown in Figure 2, nitrite levels were lowest in the hepatocytes of animals with the greatest degree of liver pathology. In general, the decrease in nitric oxide was directly proportional to the increase in liver pathology.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Emergency Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Des composés d'apport d'oxyde nitrique sont administrés à une personne pour le traitement de la prévention de maladies du foie provoquées par l'absorbtion d'alcool ou par l'ingestion d'agents pharmacologiques ou de toxines industrielles. Des exemples de composés d'apport d'oxyde nitrique comprennent S-nitrosothiols, thionitrites, thionitrates, sydnonimines, furoxanes, nitrates organiques, nitroprusside, nitroglycérine, fer-nitrosyl, ou autres composés apparentés. De plus, les maladies du foie provoquées par l'alcool peuvent également être prévenues en administrant une quantité thérapeutiquement efficace soit d'arginine, soit d'un analogue d'arginine, soit d'un composé d'apport d'oxyde nitrique, en combinaison avec une boisson alcoolisée que consomme la personne.
PCT/US1994/000970 1993-01-29 1994-01-27 Utilisation de composes d'apport d'oxyde nitrique pour le traitement ou la prevention des problemes dus a une cirrhose alcoolique du foie WO1994016740A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62327/94A AU6232794A (en) 1993-01-29 1994-01-27 The use of nitric oxide-delivering compounds for the treatment or prevention of alcoholic liver injury

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US1213593A 1993-01-29 1993-01-29
US08/012,135 1993-01-29

Publications (1)

Publication Number Publication Date
WO1994016740A1 true WO1994016740A1 (fr) 1994-08-04

Family

ID=21753553

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/000970 WO1994016740A1 (fr) 1993-01-29 1994-01-27 Utilisation de composes d'apport d'oxyde nitrique pour le traitement ou la prevention des problemes dus a une cirrhose alcoolique du foie

Country Status (2)

Country Link
AU (1) AU6232794A (fr)
WO (1) WO1994016740A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
WO2006031191A1 (fr) 2004-09-14 2006-03-23 Per Agvald Compositions comprenant des composes capables de former une liaison reversible ou une association avec l'oxyde nitrique gazeux
US7025869B2 (en) 2001-09-05 2006-04-11 Cyterra Corporation Nitric oxide delivery system
EP1718289A4 (fr) * 2004-02-24 2007-04-11 Univ Vanderbilt Methodes therapeutiques faisant appel a des precurseurs d'oxyde nitrique
WO2007121545A1 (fr) * 2006-04-20 2007-11-01 Universidade Estadual De Campinas-Unicamp Compositions contenant des s-nitrosothiols et utilisation de ces compositions
US7560076B2 (en) 2004-08-18 2009-07-14 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7618594B2 (en) 2004-08-18 2009-11-17 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7914743B2 (en) 2008-01-28 2011-03-29 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7947227B2 (en) 2007-03-23 2011-05-24 Geno Llc Kit for the conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8188147B2 (en) 1999-06-01 2012-05-29 Vanderbilt University Therapeutic methods employing nitric oxide precursors
US8607785B2 (en) 2008-08-21 2013-12-17 Geno Llc Systems and devices for generating nitric oxide
US8646445B2 (en) 2009-11-20 2014-02-11 Geno Llc Nitric oxide delivery system
WO2015017383A3 (fr) * 2013-07-31 2015-10-29 The Children's Hospital Of Philadelphia Compositions et procédés de traitement de troubles du métabolisme des acides gras
US10137103B2 (en) 2015-11-06 2018-11-27 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of fatty acid metabolism disorders
US10500181B2 (en) 2008-01-31 2019-12-10 Vanderbilt University Methods and compositions for treatment for coronary and arterial aneurysmal subarachnoid hemorrhage
WO2020109420A1 (fr) 2018-11-27 2020-06-04 Attgeno Ab Procédés de préparation de propanediols nitrosylés, compositions comprenant ceux-ci, et leurs utilisations médicales
WO2021239892A1 (fr) 2020-05-27 2021-12-02 Attgeno Ab Propanediols mono- et bis-nitrosylés à usage thérapeutique
US11485923B1 (en) 2013-03-13 2022-11-01 Airworthy Autogas, Llc Gasoline for aircraft use
US11925764B2 (en) 2009-06-22 2024-03-12 Vero Biotech Inc. Nitric oxide therapies

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3950529A (en) * 1975-02-03 1976-04-13 Massachusetts General Hospital Amino acid formulations for patients with liver disease and method of using same
US4987123A (en) * 1988-02-24 1991-01-22 Ajinomoto Co., Inc. Compositions useful for the treatment and/or prevention of hepatic disorders, and their pharmaceutical use

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3950529A (en) * 1975-02-03 1976-04-13 Massachusetts General Hospital Amino acid formulations for patients with liver disease and method of using same
US4987123A (en) * 1988-02-24 1991-01-22 Ajinomoto Co., Inc. Compositions useful for the treatment and/or prevention of hepatic disorders, and their pharmaceutical use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
R. BERKOW et al., "The Merck Manual of Diagnosis and Therapy", 14th Edition, published 1982, by MERCK SHARP & DOHME RESEARCH LABORATORIES (N.J.), pages 830-833 and 846-849. *

Cited By (58)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7087709B2 (en) 1996-08-02 2006-08-08 Duke University Polymers for delivering nitric oxide in vivo
US6403759B2 (en) 1996-08-02 2002-06-11 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
US6875840B2 (en) 1996-08-02 2005-04-05 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
US7417109B2 (en) 1996-08-02 2008-08-26 Duke University Polymers for delivering nitric oxide in vivo
US8188147B2 (en) 1999-06-01 2012-05-29 Vanderbilt University Therapeutic methods employing nitric oxide precursors
US8536225B2 (en) 1999-06-01 2013-09-17 Vanderbilt University Therapeutic methods employing nitric oxide precursors
US9486429B2 (en) 1999-06-01 2016-11-08 Vanderbilt University Therapeutic methods employing nitric oxide precursors
US7040313B2 (en) 2001-09-05 2006-05-09 Cyterra Corporation Method and apparatus for nitric oxide generation
US8066904B2 (en) 2001-09-05 2011-11-29 Geno Llc Controlled generation of nitric oxide
US8221800B2 (en) 2001-09-05 2012-07-17 Geno Llc Nitric oxide delivery system
US7025869B2 (en) 2001-09-05 2006-04-11 Cyterra Corporation Nitric oxide delivery system
US8371296B2 (en) 2001-09-05 2013-02-12 Geno, LLC Method and apparatus for nitric oxide generation
EP1718289A4 (fr) * 2004-02-24 2007-04-11 Univ Vanderbilt Methodes therapeutiques faisant appel a des precurseurs d'oxyde nitrique
JP2013040176A (ja) * 2004-02-24 2013-02-28 Vanderbilt Univ 一酸化窒素前駆体を用いる治療方法
JP2007524695A (ja) * 2004-02-24 2007-08-30 バンダービルト・ユニバーシティ 一酸化窒素前駆体を用いる治療方法
US8057742B2 (en) 2004-08-18 2011-11-15 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8246725B2 (en) 2004-08-18 2012-08-21 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8821801B2 (en) 2004-08-18 2014-09-02 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11383059B2 (en) 2004-08-18 2022-07-12 Vero Biotech Inc. Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11291793B2 (en) 2004-08-18 2022-04-05 Vero Biotech Inc. Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11554241B2 (en) 2004-08-18 2023-01-17 Vero Biotech Inc. Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8226916B2 (en) 2004-08-18 2012-07-24 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8083997B2 (en) 2004-08-18 2011-12-27 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7618594B2 (en) 2004-08-18 2009-11-17 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7560076B2 (en) 2004-08-18 2009-07-14 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US9522249B2 (en) 2004-08-18 2016-12-20 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11202880B2 (en) 2004-08-18 2021-12-21 Vero Biotech LLC Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8609028B2 (en) 2004-08-18 2013-12-17 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US10124142B2 (en) 2004-08-18 2018-11-13 Vero Biotech LLC Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
WO2006031191A1 (fr) 2004-09-14 2006-03-23 Per Agvald Compositions comprenant des composes capables de former une liaison reversible ou une association avec l'oxyde nitrique gazeux
WO2007121545A1 (fr) * 2006-04-20 2007-11-01 Universidade Estadual De Campinas-Unicamp Compositions contenant des s-nitrosothiols et utilisation de ces compositions
US7947227B2 (en) 2007-03-23 2011-05-24 Geno Llc Kit for the conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8211368B2 (en) 2007-03-23 2012-07-03 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11884541B2 (en) 2008-01-28 2024-01-30 Vero Biotech Inc. Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8741222B2 (en) 2008-01-28 2014-06-03 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US7914743B2 (en) 2008-01-28 2011-03-29 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US9701538B2 (en) 2008-01-28 2017-07-11 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8609026B2 (en) 2008-01-28 2013-12-17 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US8187544B2 (en) 2008-01-28 2012-05-29 Geno Llc Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US11312626B2 (en) 2008-01-28 2022-04-26 Vero Biotech Inc. Conversion of nitrogen dioxide (NO2) to nitric oxide (NO)
US10500181B2 (en) 2008-01-31 2019-12-10 Vanderbilt University Methods and compositions for treatment for coronary and arterial aneurysmal subarachnoid hemorrhage
US10926054B2 (en) 2008-08-21 2021-02-23 Vero Biotech LLC Systems and devices for generating nitric oxide
US12171948B2 (en) 2008-08-21 2024-12-24 Vero Biotech Inc. Systems and devices for generating nitric oxide
US11744978B2 (en) 2008-08-21 2023-09-05 Vero Biotech Inc. Systems and devices for generating nitric oxide
US8607785B2 (en) 2008-08-21 2013-12-17 Geno Llc Systems and devices for generating nitric oxide
US8944049B2 (en) 2008-08-21 2015-02-03 Geno Llc Systems and devices for generating nitric oxide
US11925764B2 (en) 2009-06-22 2024-03-12 Vero Biotech Inc. Nitric oxide therapies
US8646445B2 (en) 2009-11-20 2014-02-11 Geno Llc Nitric oxide delivery system
US11485923B1 (en) 2013-03-13 2022-11-01 Airworthy Autogas, Llc Gasoline for aircraft use
WO2015017383A3 (fr) * 2013-07-31 2015-10-29 The Children's Hospital Of Philadelphia Compositions et procédés de traitement de troubles du métabolisme des acides gras
US10434079B2 (en) 2013-07-31 2019-10-08 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of fatty acid metabolism disorders
US10137103B2 (en) 2015-11-06 2018-11-27 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of fatty acid metabolism disorders
US10590063B2 (en) 2015-11-06 2020-03-17 The Children's Hospital Of Philadelphia Compositions and methods for the treatment of fatty acid metabolism disorders
WO2020109420A1 (fr) 2018-11-27 2020-06-04 Attgeno Ab Procédés de préparation de propanediols nitrosylés, compositions comprenant ceux-ci, et leurs utilisations médicales
EP4450069A2 (fr) 2018-11-27 2024-10-23 Attgeno AB Procedes de preparation de propanediols nitrosyles, compositions les comprenant et utilisations medicales de ceux-ci
WO2021239892A1 (fr) 2020-05-27 2021-12-02 Attgeno Ab Propanediols mono- et bis-nitrosylés à usage thérapeutique

Also Published As

Publication number Publication date
AU6232794A (en) 1994-08-15

Similar Documents

Publication Publication Date Title
WO1994016740A1 (fr) Utilisation de composes d'apport d'oxyde nitrique pour le traitement ou la prevention des problemes dus a une cirrhose alcoolique du foie
Kuo et al. The emerging multifaceted roles of nitric oxide
Otterbein et al. Mechanism of hemoglobin-induced protection against endotoxemia in rats: a ferritin-independent pathway
US5578637A (en) Methods of inhibition or killing cancer cells using an endoperoxide
Clark et al. The clinical pharmacology of etoposide and teniposide
US5545614A (en) Controlling nitrogen oxide concentrations to modulate skeletal muscle contraction
EP1773312B1 (fr) Composition contenant des statines et des acides gras 3
US5380758A (en) S-nitrosothiols as smooth muscle relaxants and therapeutic uses thereof
US20050070607A1 (en) N-acetylcysteine compositions and methods for the treatment and prevention of cysteine/glutathione deficiency in diseases and conditions
US6231894B1 (en) Treatments based on discovery that nitric oxide synthase is a paraquat diaphorase
CN101115505A (zh) 治疗由过氧亚硝酸盐过度表达引起的哺乳动物疾病和创伤的方法和组合物
Gibaldi What is nitric oxide and why are so many people studying it?
JP2002518443A (ja) 一酸化窒素源の治療的投与に起因する副作用を治療するための一酸化窒素捕捉剤の使用
Shinde et al. Nitric oxide: a molecule of the millennium
WO1993012068A1 (fr) S-nitrosothiols utilises comme decontracturants des muscles lisses et leurs utilisations therapeutiques
US20060183798A1 (en) Method for preventing and/or treating peripheral neuropathies induced by the administration of an anticancer agent
JP2001518096A (ja) アポトーシス性酵素を不活性化するためのニトロシル化
Allen et al. Nitric oxide synthase inhibitors exert differential time-dependent effects on LPS-induced uveitis
Holme et al. Effects of pivalic acid-containing prodrugs on carnitine homeostasis and on response to fasting in children
EP1708739A1 (fr) Complexe neuroprotecteur destine au traitement de l'ischemie et de lesions cerebrales
WO1996031217A9 (fr) Inhibition de la replication des retrovirus
Eriksson et al. Effects of inorganic nitrate on ischaemia-reperfusion injury after coronary artery bypass surgery: a randomised controlled trial
US5767103A (en) Nitric oxide sequestrant
RU2006142101A (ru) Способ снижения желудочно-кишечной токсичности, возникающей в результате применения тегафура
US6346634B1 (en) Chemical compound containing a superoxide scavenger and an organic nitrate or nitrite moiety

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA JP

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载