WO1994022306A1 - Therapie combinee a l'oxyde nitrique - Google Patents

Therapie combinee a l'oxyde nitrique Download PDF

Info

Publication number
WO1994022306A1
WO1994022306A1 PCT/US1994/003562 US9403562W WO9422306A1 WO 1994022306 A1 WO1994022306 A1 WO 1994022306A1 US 9403562 W US9403562 W US 9403562W WO 9422306 A1 WO9422306 A1 WO 9422306A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitric oxide
compound
administered
neutralizing compound
composition
Prior art date
Application number
PCT/US1994/003562
Other languages
English (en)
Inventor
Jonathan S. Stamler
Original Assignee
Brigham And Womens 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 Womens Hospital filed Critical Brigham And Womens Hospital
Priority to AU65284/94A priority Critical patent/AU6528494A/en
Publication of WO1994022306A1 publication Critical patent/WO1994022306A1/fr

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/556—Angiotensin converting enzyme inhibitors

Definitions

  • nitric oxide is exceedingly unstable, reacting essentially instantaneously with oxygen, superoxide anion, and redox metals (Lancaster et al., Proc. Natl. Acad. Sci. USA. 87:1223-1227 (1990); Ignarro et al., Circ. Res. 5_:1-21 (1989); and Gryjglewski et al., Nature 320:454-456 (1986)).
  • NO production in the lung is not known. However, it has been believed that potential beneficial bronchodilation effects of NO may be counterbalanced by generation of toxic nitrogen oxides that form readily under the high ambient concentration of oxygen and other reactive oxygen species.
  • Introduction of NO into the lungs has been associated by some with adverse effects, which occur as a direct result of the particular chemical reactivity of the uncharged NO radical (NO").
  • NO uncharged NO radical
  • These adverse effects create impediments to NO therapy which generally involves administration of NO' .
  • the reaction between NO", and 0- or reactive O, species which are present in high concentrations in the lung generates highly toxic products, such as NO, and peroxynitrite. These reactions also result in the rapid inactivation of NO, thus allegedly eliminating any beneficial pharmacological effect.
  • Zapol and Frostell PCT Publication No. WO 92/10228 discloses a method for treating or preventing bronchoconstriction, e.g., asthma or reversible pulmonary vasoconstriction, e.g., pulmonary hypertension, by inhalation of gaseous nitric oxide or nitric oxide-releasing compounds. Many such compounds are known. These investigators characterize the mammalian circulatory system as consisting of two separate circuits, the systemic circuit and the pulmonary circuit which are controlled by opposite sides of the heart.
  • bronchodilating and pulmonary vasodilating methods are important advantages of their bronchodilating and pulmonary vasodilating methods.
  • the rapid binding of NO to hemoglobin ensures that any vasodilatory action of inhaled NO is solely a local or selective effect in the blood vessels of the lung, with no concomitant vasodilation downstream in the systemic circulation.
  • a method of treating an individual in need of treatment with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
  • the neutralizing compound is preferably administered concurrently with nitric oxide administration, preferably by the inhalation route, e.g., in mixture with the nitric oxide, or intravenously, and is preferably a thiol.
  • the invention is based on the discovery by the inventor that thiols, e.g. N-acetylcyteine, or precursors of glulathione synthesis react with NO (where x is 2 or more) to prevent toxicity thereof to the lung.
  • thiols e.g. N-acetylcyteine
  • NO where x is 2 or more
  • compounds can be administered in accordance with the invention that upregulate the body's production of thiols, e.g. glutathione.
  • thiol refers to a compound which is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine and captopril.
  • thiol refers to particular long carbon-chain lipophilic thiols.
  • the invention relates to a method for treatment of an individual in need thereof with nitric oxide which comprises (i) administering by the inhalation route a therapeutically effective amount of nitric oxide and (ii) administering a compound that neutralizes toxic species to which nitric oxide spontaneously oxidizes.
  • the invention in another aspect, relates to a composition for treating an individual in need of treatment with nitric oxide which comprises (i) an inhalable preparation of a therapeutically effective amount of nitric oxide and (ii) a compound that neutralizes toxic species to which nitric oxide spontaneously oxides.
  • the neutralizing compound is preferably in an inhalable preparation, e.g. in mixture with the nitric oxide, or is in an intravenous preparation.
  • the neutralizing compound is preferably a thiol.
  • the thiol is selected from the group consisting of N-acetylcysteine, glutathione, cysteine, homocysteine, pantathoeine derivatives, penicillamine, captopril and long carbon-chain lipophilic thiols.
  • Modes of administration include but are not limited to intravenous, intranasal, and oral routes.
  • the compounds may be administered by, for example, by infusion or bolus injection and may be administered together with other biologically active agents.
  • compositions comprise a therapeutically effective amount of a therapeutic, and a pharmaceutically acceptable carrier or excipient.
  • a pharmaceutically acceptable carrier includes but is not limited to physiologically acceptable gases and mixtures thereof and liquid carriers such as saline, buffered saline, dextrose, water, and combinations thereof.
  • the formulation should suit the mode of administration.
  • the composition is formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to human beings.
  • compositions for intravenous administration are solutions in sterile isotonic aqueous buffer.
  • the composition may also include a solubilizing agent and a local anesthetic to ameliorate any pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • the composition is to be administered by infusion, it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.
  • the amount of the neutralizing compound which will be effective in combination with the nitric oxide will depend on the level and duration of the nitric oxide administered, and can be determined by standard clinical techniques without undue experimentation.
  • the precise dose of the neutralizing compound to be employed in the formulation will also depend on the route of administration, and should be decided according to the judgment of the practitioner and each patient's circumstances.
  • suitable dosage ranges for intravenous or nebulized inhalation administration are generally about up to about 200 milligrams of neutralizing compound per kilogram body weight. Alternatively, doses of up to about 50 mg/kg can be administered up to about 6 times per day.
  • Suitable dosage ranges for inhalation administration of nitric oxide include at least those disclosed in Zapol and Frostell, PCT Publication No. WO 92/10228.
  • the invention also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions of the invention.
  • Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.

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)
  • Vascular Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

On diminue les effets néfastes de l'oxyde nitreux et d'autres états d'oxydation elevés de l'oxyde nitrique, même à des niveaux d'oxyde nitrique elevés administrés par inhalation, en soumettant le sujet à un traitement à l'oxyde nitrique par inhalation, puis en lui administrant un composé qui neutralise les espèces toxiques sur lesquelles l'oxyde nitrique s'oxyde spontanément. Le composé de neutralisation est de préférence administré en même temps que l'oxyde nitrique, de préférence par inhalation, par exemple mélangé à l'oxyde nitrique, ou par voie intraveineuse, et il est de préférence constitué par un thiol.
PCT/US1994/003562 1993-04-06 1994-03-31 Therapie combinee a l'oxyde nitrique WO1994022306A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU65284/94A AU6528494A (en) 1993-04-06 1994-03-31 Nitric oxide combination therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4436793A 1993-04-06 1993-04-06
US08/044,367 1993-04-06

Publications (1)

Publication Number Publication Date
WO1994022306A1 true WO1994022306A1 (fr) 1994-10-13

Family

ID=21931992

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1994/003562 WO1994022306A1 (fr) 1993-04-06 1994-03-31 Therapie combinee a l'oxyde nitrique

Country Status (2)

Country Link
AU (1) AU6528494A (fr)
WO (1) WO1994022306A1 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1018984A1 (fr) * 1997-06-26 2000-07-19 Cordis Corporation DISPOSITIF MEDICAL CON U POUR LA LIBERATION DU MONOXYDE D'AZOTE $i(IN VIVO)
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6232434B1 (en) 1996-08-02 2001-05-15 Duke University Medical Center Polymers for delivering nitric oxide in vivo
EP1301076A2 (fr) * 2000-06-28 2003-04-16 The General Hospital Corporation Methodes ameliorant l'efficacite therapeutique du monoxyde d'azote administre par inhalation
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
WO2018053397A1 (fr) * 2016-09-16 2018-03-22 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Méthodes de traitement ou de prévention d'empoisonnement par un organophosphate
WO2023173141A3 (fr) * 2022-03-11 2023-11-16 Loma Linda University Compositions et méthodes de traitement d'une maladie à l'aide d'une combinaison d'un nitrodilatateur et d'un composé d'oxyde d'azote

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MEDLINE, Abstract, Vol. 90, No. 2, issued August 1992, DUPY et al., "Bronchodilator Action of Inhaled Nitrix Oxide", see abstract no. 92355776; & J. CLIN. INVEST., (Aug 1992), 90(12). *

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6855691B1 (en) 1995-09-15 2005-02-15 Duke University Methods for producing and using S-nitrosohemoglobins
US6153186A (en) * 1995-09-15 2000-11-28 Duke University Medical Center Red blood cells loaded with S-nitrosothiol and uses therefor
US6197745B1 (en) 1995-09-15 2001-03-06 Duke University Methods for producing nitrosated hemoglobins and therapeutic uses therefor
US6203789B1 (en) 1995-09-15 2001-03-20 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US7538193B2 (en) 1995-09-15 2009-05-26 Duke University NO-modified hemoglobins and uses therefor
US7202340B2 (en) 1995-09-15 2007-04-10 Duke University No-modified hemoglobins and uses therefor
US6916471B2 (en) 1995-09-15 2005-07-12 Duke University Red blood cells loaded with S-nitrosothiol and uses therefor
US6911427B1 (en) 1995-09-15 2005-06-28 Duke University No-modified hemoglobins and uses therefore
US6627738B2 (en) 1995-09-15 2003-09-30 Duke University No-modified hemoglobins and uses therefor
US6884773B1 (en) 1995-09-15 2005-04-26 Duke University Modified hemoglobins, including nitrosylhemoglobins, and uses thereof
US6875840B2 (en) 1996-08-02 2005-04-05 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
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
US7087709B2 (en) 1996-08-02 2006-08-08 Duke University Polymers for delivering nitric oxide in vivo
EP1018984A1 (fr) * 1997-06-26 2000-07-19 Cordis Corporation DISPOSITIF MEDICAL CON U POUR LA LIBERATION DU MONOXYDE D'AZOTE $i(IN VIVO)
EP1018984A4 (fr) * 1997-06-26 2003-03-12 Cordis Corp DISPOSITIF MEDICAL CON U POUR LA LIBERATION DU MONOXYDE D'AZOTE $i(IN VIVO)
EP1301076A2 (fr) * 2000-06-28 2003-04-16 The General Hospital Corporation Methodes ameliorant l'efficacite therapeutique du monoxyde d'azote administre par inhalation
AU2001273622B2 (en) * 2000-06-28 2007-05-10 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
KR100849103B1 (ko) * 2000-06-28 2008-07-30 더 제너럴 하스피탈 코포레이션 산화질소 흡입의 치료 효능 향상
US6935334B2 (en) 2000-06-28 2005-08-30 The General Hospital Corporation Enhancing therapeutic effectiveness of nitric oxide inhalation
EP1301076A4 (fr) * 2000-06-28 2004-09-22 Gen Hospital Corp Methodes ameliorant l'efficacite therapeutique du monoxyde d'azote administre par inhalation
WO2018053397A1 (fr) * 2016-09-16 2018-03-22 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Méthodes de traitement ou de prévention d'empoisonnement par un organophosphate
US11291637B2 (en) 2016-09-16 2022-04-05 The Henry M. Jackson Foundation For The Advancement Of Military Medicine, Inc. Methods for treating or preventing organophosphate poisoning
WO2023173141A3 (fr) * 2022-03-11 2023-11-16 Loma Linda University Compositions et méthodes de traitement d'une maladie à l'aide d'une combinaison d'un nitrodilatateur et d'un composé d'oxyde d'azote

Also Published As

Publication number Publication date
AU6528494A (en) 1994-10-24

Similar Documents

Publication Publication Date Title
EP0692984B1 (fr) Effets systemiques de l'inhalation de l'oxyde nitrique
EP0914103B1 (fr) Traitement d'un type d'hemoglobinose
AU751853B2 (en) Use of inhaled NO as anti-inflammatory agent
CA2383174C (fr) Techniques de traitement de maladies cardio-respiratoires a l'aide de composes renfermant un groupe no
EP1516639B1 (fr) Utilisation de NO pour le traitement de la hypertension pulmonaire persistante du nouveau-né
US20050197281A1 (en) Pharmaceutical combination preparations containing erythropoietin and modified haemoglobins
WO1994022306A1 (fr) Therapie combinee a l'oxyde nitrique
WO2002064026A2 (fr) Traitement d'affections pulmonaires a l'aide d'un agent gazeux provoquant une saturation de gsno
WO2005077005A2 (fr) Amelioration de l'efficacite d'un gaz therapeutique inhale
KR19990022586A (ko) 혈관 산화질소 저장기로서의 액체 플루오로카본에멀젼
AU690109C (en) Systemic effects of nitric oxide inhalation
EP1214933A1 (fr) Procede pour moduler le metabolisme des oxydes d'azote, composition correspondante et ses variantes et procede pour agir sur l'organisme d'un patient necessitant une correction du metabolisme des oxydes d'azote
CA2213188C (fr) Traitement de la restenose et de la thrombose vasculaires a l'aide d'oxyde nitrique inhale
EP1712226A2 (fr) Traitement d'un Hemoglobinopathy
AU2002237784A1 (en) Treating pulmonary disorders with gaseous agent causing repletion of GSNO

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